Anti-Aging: State of the Art

by JackH11 min read31st Dec 2020151 comments

250

Life ExtensionAgingWorld Optimization
Curated

Aging is a problem that ought to be solved, and most Less Wrongers recognize this. However, few members of the community seem to be aware of the current state of the anti-aging field, and how close we are to developing effective anti-aging therapies. As a result, there is a much greater (and in my opinion, irrational) overemphasis on the Plan B of cryonics for life extension, rather than Plan A of solving aging. Both are important, but the latter is under-emphasised despite being a potentially more feasible strategy for life extension given the potentially high probability that cryonics will not work.

Today, there are over 130 longevity biotechnology companies and over 50 anti-aging drugs in clinical trials in humans. The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans. Whether we live to see anti-aging therapies to keep us alive indefinitely (i.e. whether we make it to longevity escape velocity) depends on how much traction and funding the field gets in coming decades. 

In this post, I summarise the state of the art of the anti-aging field (also known as longevity biotechnology, rejuvenation biotechnology, translational biogerontology or geroscience). If you feel you already possess the necessary background on aging, feel free to skip to Part V. 

 

Part I: Why is Aging a problem?

Aging is the biggest killer worldwide, and also the largest source of morbidity. Aging kills 100,000 people per day; more than twice the sum of all other causes of death. This equates to 37 million people - a population the size of Canada - dying per year of aging. In developed countries, 9 out of 10 deaths are due to aging. 

Aging also accounts for more than 30% of all disability-adjusted life years lost (DALYs); more than any other single cause. Deaths due to aging are not usually quick and painless, but preceded by 10-15 years of chronic illnesses such as cancer, type 2 diabetes and Alzheimer’s disease. Quality of life typically deteriorates in older age, and the highest rates of depression worldwide are among the elderly

To give a relevant example of the effects of aging, consider that aging is primarily responsible for almost all COVID-19 deaths. This is observable in the strong association of COVID-19 mortality with age (below, middle panel):  

The death rate from COVID-19 increases exponentially with age (above, middle). This is not a coincidence - it is because biological aging weakens the immune system and results in a much higher chance of death from COVID-19. On a side note, waning immunity with age also increases cancer risk, as another example of how aging is associated with chronic illness.

The mortality rate doubling time for COVID-19 is close to the all-cause mortality rate doubling time, suggesting that people who die of COVID-19 are really dying of aging. Without aging, COVID-19 would not be a global pandemic, since the death rate in individuals below 30 years old is extremely low

 

Part II: What does a world without aging look like? 

For those who have broken free of the pro-aging trance and recognise aging as a problem, there is the further challenge of imagining a world without aging. The prominent ‘black mirror’ portrayals of immortality as a curse or hubristic may distort our model of what a world with anti-aging actually looks like.

The 'white mirror' of aging is a world in which biological age is halted at 20-30 years, and people maintain optimal health for a much longer or indefinite period of time. Although people will still age chronologically (exist over time) they will not undergo physical and cognitive decline associated with biological aging. At chronological ages of 70s, 80s, even 200s, they would maintain the physical appearance and much lower disease risk of a 20-30-year-old.

This may sound like science fiction but is a phenomenon exhibited by other species such as hydras, naked mole rats, tortoises, whales, and sharks - the latter of which can live up to 400 years old. While these species do eventually die, their risk of disease does not change over time - a phenomenon known as 'negligible senescence' - and these species do not age. In contrast, as humans, we experience an exponentially increasing risk of death over time due to aging, a phenomenon known as Gompertz law. Yet this law is not an ingrained law of biology or the result of entropy, as it does not apply to other species, and the goal of anti-aging is to attain negligible senescence in humans. 

There would be many benefits to an ageless population such as:

  • Very low rates of cancer, heart disease, Alzheimer’s disease etc.
  • Increased healthy lifespans
  • Increased cognitive function in older age
  • Lower death rates globally
  • Trillions of dollars saved on healthcare systems globally

Transitioning to an ageless population would come with several social implications that will need to be considered such as overpopulation, climate impact, immortal dictators and distributional justice. I’ll save a deeper discussion of these for a future post, but you can read responses to these objections here and by Aubrey de Grey, David Wood and others. 

 

Part III: What is aging?

Aging is essentially damage that accumulates over time, which exponentially increases the risk of the diseases that kill most people (shown below): 

This 'damage' associated with aging comes in essentially 9 forms, known as the hallmarks of aging

  • Genomic instability
  • Telomere attrition
  • Epigenetic alterations
  • Loss of proteostasis
  • Deregulated nutrient-sensing
  • Mitochondrial dysfunction
  • Cellular senescence
  • Stem cell exhaustion
  • Altered intercellular communication

The hallmarks of aging are shown in the context of the cellular and extracellular microenvironment are depicted below:

These forms of cellular damage drive the increased risk of disease, frailty, cognitive decline as well as observable signs of aging such as grey hair, frailty and wrinkles. I'm going to save a deeper discussion of the hallmarks and their link to chronic diseases for a future post, but for excellent reviews on this topic I recommend this, this and this

 

Where does this ‘damage’ come from?

The 'damage' (hallmarks of aging) occurs as a by-product of normal metabolism - the biochemical reactions that keep us alive. More and more damage accumulates and eventually leads to pathology, i.e. disease. When we talk about anti-aging we are talking about fixing the damage using an engineering approach before it accumulates to a dangerous level at which diseases emerge. 

The 'engineering' approach of geroscience aims to combat aging by ameliorating the damage associated with aging before it causes pathology. The engineering approach differs from gerontology which aims to intervene by altering metabolism, but fails since metabolism is essentially too complicated for us to intervene in. It also differs from geriatrics, which aims to intervene once the damage has already accumulated and the disease is emerging but fails since it intervenes too late. Source: here.

This basic model of aging can be understood as similar to the damage accumulated by a car. In its normal use, a car accrues damage that increases the likelihood that it will break down. Anti-aging is equivalent to maintaining a car, to prevent it from breaking down in the first place. 

 

Anti-aging vs current medicine

Anti-aging is more feasible for extending healthy lifespan rather than solving the individual diseases of aging due to Taueber’s paradox and the highly comorbid nature of age-related diseases. Even if a person survives one age-related disease such as cancer, another (e.g. diabetes, cardiovascular disease) will kill them if aging is not solved. This accounts for the much smaller increase in healthy lifespan associated with curing the diseases of aging, such as cancer (2-3 years), versus slowing aging itself (30+ years):

Slowing aging is more effective than curing disease. Displayed are the calculated impacts on life expectancy for a typical 50-year-old woman from curing cancer, heart disease, or both, relative to the impact of slowing aging. The figure was generated from data presented in Lombard et al. (2016). The coloring illustrates the hypothetical impact on health expectancy in each case, where green represents the absence of a comorbidity and red represents a severe comorbidity. Source here

 

The difference between anti-aging and current medicine is the former prevents illness by targeting the hallmarks of aging, whereas the latter intervenes once a disease has emerged. If we compare current medical interventions associated with geriatrics with anti-aging - the former extends unhealthy lifespan, whereas only the latter extends healthy lifespan. 

Therefore, there is strong reason to think that anti-aging will be more successful in extending healthy lifespan than the ‘sick-care’ approach of current medicine

 

Part IV: Can aging actually be slowed?

In the lab, we have demonstrated that various anti-aging approaches can extend healthy lifespan in many model organisms including yeast, worms, fish, flies, mice and rats. Life extension of model organisms using anti-aging approaches ranges from 30% to 1000%

The methuselahs in lab: The increase in maximum lifespan in the laboratory is shown in 5 animal species, both without any interventions, and by dietary, chemical, or genetic interventions. For each organism, the impact of the increase in maximum lifespan through intervention is indicated in the graph using fold change. Source here

These results demonstrate that aging is plastic, and not a fixed process. In mice, some of the most effective approaches to life extension are summarised below:

Source: here

The plasticity of aging in model organisms that share similar metabolic physiology to us provides us good proof-of-principle that aging can be slowed in humans. It remains to be seen how much life extension is possible, and improved biomarkers of aging will be needed to accurately measure the effectiveness of new therapies in a reasonable time-frame. 

 

Part V: Most promising anti-aging strategies 

The past 5 years of research have demonstrated several anti-aging strategies as particularly promising. The diagram below, taken from a 2019 review by researchers at Stanford University summarises four of the most promising approaches to slow or reverse aging in humans, based on studies in mice:  

A comparison of the four emerging rejuvenation strategies: blood factors, metabolic manipulation, ablation of senescent cells and cellular reprogramming. The figure depicts the features that improve when treatment in mice is initiated at midlife or later. The top panel shows organs or tissues that exhibit a rejuvenated phenotype in wild-type (WT) mice. For rapamycin, features that have been shown to improve also in young mice following treatment are indicated with an asterisk (*). The effect on lifespan, proposed primary mode (or modes) of action and possible trade-offs of these strategies are also presented. Finally, the translational potential in humans is indicated by the increasing number of plus signs (+) based on present evidence in human ageing and current feasibility. NT, not tested. Question marks indicate possible modes of action and trade-offs. Original source here

The above diagram may be quite technical for non-biomedical scientists, so I'll briefly describe the approaches individually in simpler terms. Note that each of these strategies helps to reverse one or more of the hallmarks of aging.

 

1. Parabiosis (blood exchange)

Parabiosis (heterochronic parabiosis) is putting young blood into old mice, to make the old mice biologically younger. This is achieved in the lab by connecting the circulatory systems of young mice and old mice. Certain factors in the blood help to rejuvenate muscle, heart brain and liver tissues in old mice and restore their biological function. 

Equivalent procedures that modify the compounds within blood in humans such as apheresis (blood filtering) could be used to slow aging in humans and thereby prevent or slow the progression of many types of age-related diseases including Alzheimer's disease

Recently, a group of Russian biohackers recently took part in the first plasma dilution experiments in humans. In a research context, the safety and effectiveness of apheresis is being tested in a clinical trial in humans by the company Alkahest. 

Hallmarks reversed: parabiosis reverses age-related decline by targeting several hallmarks of aging including stem cell exhaustion, cellular senescence and altered intercellular communication (inflammation).

 

2. Metabolic manipulation (mTOR inhibitors)

Dietary restriction has been shown to extend healthy lifespan across several species. Drugs that mimic the metabolic effects of dietary restriction also have beneficial effects on lifespan. Nutrient-sensing biochemical pathways (such as IGF-1, mTOR and AMPK) play a key role in these effects. Metformin is a drug that is FDA-approved for diabetes that extends healthy lifespan in mice by inhibiting mTOR and activating autophagy. Metformin is currently being tested in a large clinical trial in humans to test its anti-aging properties.

Source: here

Hallmarks of aging targeted: The widespread mechanisms of action of metformin help to improve all of the 9 hallmarks of aging, shown below. I'll save the details for those interested, who can read a more thorough review here

Source: here.

Another promising drug that manipulates metabolism is rapamycin (also known as siromilus), an FDA-approved immunosuppressant that extends healthy lifespan in mice and similarly acts to inhibit mTOR. Rapamycin is currently in a clinical trial in humans to test its anti-aging properties. 

 

3. Senolytics - drugs that kill senescent cells

Senescent cells are a kind of 'zombie'-like cell that accumulate with age. They are death-resistant cells that secrete proinflammatory factors associated with a range of age-related diseases (below, right):  

Cellular senescence is associated with multiple human disorders. The development of galactose‐conjugated and fluorescent probes to detect and highlight senescent cells offers an important opportunity for longitudinal monitoring of senescence in clinical trials. Pharmacologically active small compounds known as senolytics inhibit pro‐survival pathways in senescent cells leading to apoptosis, a therapeutic strategy that may additionally be enhanced by the use of immune modulators promoting natural clearance of senescent cells. Finally, nanoparticles encapsulating cytotoxic drugs, tracers and/or small molecules can be used as theranostic tools, both for therapeutic and diagnostic purposes. Source: here 

There are various strategies being explored to kill or reprogram senescent cells (above, left), including senolytics. Senolytics are drugs that kill senescent cells to improve physical function and healthy lifespan. When administered to older mice, senolytics have been shown to reverse many aspects of aging such as cataracts, and arthritis (below): 

Killing senescent cells with senolytics extends the median healthy lifespan by up to 27% in mice (below). Several senolytics, such as the combination of dasatinib and quercetin, and fisetin are in clinical trials in humans today. 

Study design for clearance of senescent cells mouse cohort. Median survival (in days, d) and percentage increase in median survival are indicated. Source: here

Hallmarks of aging reversed: senolytics decelerate cellular senescence, improve epigenetic markers and restore intercellular communication (by reducing inflammation associated with senescent cells) to extend healthy lifespan. 

 

4. Cellular reprogramming 

Cellular reprogramming is the conversion of terminally differentiated cells (old cells) into induced pluripotent stem cells (IPSCs) (‘young’ cells). Cells can be re-programmed to a youthful state using a cocktail of 4 factors known as Yamanaka factors, a finding for which a Nobel prize was awarded in 2012

Induced pluripotent stem cells (IPSCs) have essentially unlimited regenerative capacity and carry the promise for tissue replacement to counter age-related decline. Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer

(A) The diagram depicts cellular programming to pluripotency, in other words, the conversion of terminally differentiated somatic cells into induced pluripotent stem cells (iPSCs) by cellular reprogramming through forced expression of Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc). (B) The diagram depicts the rejuvenation of aged cells by cellular reprogramming. The process results in the amelioration of hallmarks of aging such as mitochondrial dysfunction, shortening of telomere length, changes in epigenetic marks, increased DNA damage, and senescence. Source: here

An impressive example of cellular reprogramming was the restoration of vision in blind mice with a severed optic nerve using 3 of the 4 Yamanaka factors. The researchers from Harvard Medical School were able to regrow a fully functioning optic nerve in mice using cellular reprogramming. This approach could be used in future to regenerate other tissues as a new anti-aging strategy. 

Using the eye as a model tissue, expression of Oct4, Sox2 and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. Source: here

Hallmarks of aging targeted: Cellular reprogramming has been shown to reverse many of the hallmarks of aging, such as mitochondrial dysfunction, shortening of telomere length, changes in epigenetic marks, genomic instability, and cellular senescence.

 

5. Additional anti-aging approaches

Although not covered here, there are many other promising strategies for rejuvenation including thymic rejuvenation which has been shown to reverse biological age in humans, sirtuin enzyme activation with drugs such as resveratrol, and boosting mitochondrial function with NAD+ precursor molecules. All of these show the potential to increase healthy lifespan by targeting the hallmarks of aging. 

 

Part VI: Conclusion

Aging is essentially damage accumulation that occurs as a by-product of metabolism and causes the diseases that kill most people today. This damage comes in 9 forms, which are the hallmarks of aging. Many therapeutic strategies show great promise in extending healthy human lifespan by reversing the damage accumulated with aging. Four of the most promising strategies to extend lifespan in humans include parabiosis, metabolic manipulation, senolytics, and cellular reprogramming. 

 

Part VII: Call to Action

For those wanting to help aging  be solved in our lifetime so we can avoid being the last generation to die, consider taking the following actions:

 

Part VIII: Learn more

Books:

Ending Aging (2007) - Aubrey de Grey, PhD

Lifespan (2019) - Prof. David Sinclair, PhD

Age Later (2020) - Dr Nir Barzilai, PhD

Ageless (2020) - Andrew Steele, PhD

The Abolition of Aging (2016) - David Wood

 

YouTube:

Any talks by Prof David Sinclair, Dr Aubrey de Grey, Prof Brian Kennedy, or Dr Nir Barzilai for anti-aging science. For personal longevity strategies, I recommend talks by Dr Rhonda Patrick, Dave Asprey and Dr Peter Attia. 

You can also follow the Oxford Society of Ageing and Longevity channel here

 

Websites and blogs:

https://www.reddit.com/r/longevity

https://www.lifespan.io/

https://www.fightaging.org/

https://www.longevity.technology/

 

Good review articles:

The hallmarks of aging (2013) 

Geroscience: linking aging to chronic disease (2014)

The business of anti-aging science (2017)

Turning back time with emerging rejuvenation strategies (2019)

From discoveries in aging research to therapeutics for healthy aging (2019)

 

If you wish to contact me outside this forum, please email me at jtt.harley@gmail.com


Edit: 
Based on recommendations in the comments, I've added a short bio, below. 

About me: 
I'm not a geroscience researcher, but I am conducting neuroscience research at Oxford University after finishing my studies here and have a reasonable grasp of the geroscience field. I am vice president of the Oxford Society of Ageing and Longevity and in this role have had the privilege of interviewing influential figures in the field such as Aubrey de Grey, and researchers in the field such as  Joao Pedro de Magalhaes. I've also had meetings with many other key figures in the field including David Sinclair. I have attended most of the major conferences in the field (ARDD2020, EARD2020, CSL Mechanisms of Aging 2020 etc.) last year, and read over 1000 academic papers in this field. I have also been been invited to give guest lectures on this topic at Oxford University and Monash University, Australia. I've been a content writer at Mindset Health for 2 years so I have some background in science communication. 

250

149 comments, sorted by Highlighting new comments since Today at 1:10 PM
New Comment
Some comments are truncated due to high volume. (⌘F to expand all)Change truncation settings

As an effective altruist, I like to analyze how altruistic cause areas fare on three different axes: importance, tractability and neglectedness. The arguments you gave for the importance of aging are compelling to me (at least from a short-term, human-focused perspective). I'm less convinced that anti-aging efforts are worth it according to the other axes, and I'll explain some of my reasons here.

The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans.
[...]
In the lab, we have demonstrated that various anti-aging approaches can extend healthy lifespan in many model organisms including yeast, worms, fish, flies, mice and rats. Life extension of model organisms using anti-aging approaches ranges from 30% to 1000%

When looking at the graph you present, a clear trend emerges: the more complex and larger the organism, the less progress we have made on slowing aging for that organism. Given that humans are much more complex and larger than the model organisms you presented, I'd caution against extrapolating lab results to them.

I once heard from a cancer researcher that we had, for all ... (read more)

I am also an effective altruist and have been involved in the movement since 2012. I and others think that anti-aging and donating to SENS is probably a more important cause area than most EA cause areas (especially short-term ones) besides X-risk for the reasons below. 

As a side note, from the longer (200+ comment) discussion about anti-aging from an EA perspective on the EA Facebook group here, the main objection that held weight seemed to be 'bang for buck', and is also addressed below. 

In this piece: Why SENS Makes Sense and this piece: A general framework for evaluating aging research. Part 1: reasoning with Longevity Escape Velocity Emanuale Ascani evaluates the cost effectiveness of anti-aging, and donations to SENS Research Foundation using the EA criteria of scale, neglectedness and tractability. His estimation of cost-effectiveness of a SENS donation is $2.50 per 1000 quality-adjusted years life years saved, which dwarfs most other short-term cause areas in EA.

In terms of tractability and neglectedness, I'll add a few more thoughts:

(1) Tractability

I understand that considering the models of aging (mice, flies, yeast etc.) alone might give the impression that the... (read more)

9Matthew Barnett22dI appreciate the detailed and thoughtful reply. :) I agree that anti-aging is neglected in EA compared to other short-term, human focused cause areas. The reason is likely because the people who would be most receptive to anti-aging move to other fields. As Pablo Stafforini said [https://www.reddit.com/r/EffectiveAltruism/comments/dyyd1y/how_come_i_see_so_little_longevity_research_in/f84ht0o/?context=3] , I wrote a post about how anti-aging might be competitive with longtermist charities here [https://forum.effectivealtruism.org/posts/LxmJJobC6DEneYSWB/effects-of-anti-aging-research-on-the-long-term-future] . Again, this is nice, and I think it's good evidence that we could achieve modest success in the coming decades. But in the post you painted a different picture. Specifically, you said, If humans make continuous progress, then eventually we'll get here. I have no issue with that prediction. But my objection concerned the pace and tractability of research. And it seems like there's going to be a ton of work going from modest treatments for aging to full cures. One possible response is that the pace of research will soon speed up dramatically. Aubrey de Grey has argued along these lines on several occasions. In his opinion, there will be a point at which humanity wakes up from its pro-aging trance [https://www.metaculus.com/questions/3458/will-there-be-a-culturally-significant-development-in-aging-research-by-2030/] . From this perspective, the primary value of research in the present is to advance the timeline when humanity wakes up and gets started on anti-aging for real. Unfortunately, I see no strong evidence for this theory. People's minds tend to change gradually in response to gradual technological change. The researchers who said this year that "I'll wait until you have robust mouse rejuvenation" will just say "I'll wait until you have results in humans" when you have results in mice. [https://www.lesswrong.com/posts/LNKh22Crr5ujT85YM/after-critical
9JackH21dI agree with Pablo's reasoning as to why anti-aging has not taken off in the EA community. I agree that the 'white mirror' scenario might be some time off (even 100+ or 1000+ years away), but remember that we only need to reach longevity escape velocity for everyone on Earth to make it to the 'white mirror' scenario, not reach the 'white mirror' scenario right away. For example, within the next 50 years, we might have drugs that keep us alive for another 100 years, meaning even if it takes 80 years to develop drugs that keep us alive for 1000 years, and then it takes 800 years for us to develop drugs that would bring us to the 'white mirror' scenario, we would still reach it. This is the beauty of longevity escape velocity - we only need drugs that keep us alive until better drugs arrive, to stay alive indefinitely and reach the 'white mirror' scenario. I, and many others in the field, would disagree with you here for a simple reason: once we start getting drugs that work, and good evidence that they work - for example, a drug that prevents cancer - people will take them. People generally care about their health enough to take medicines that improve/protect their health - for example, vaccines, statins, cancer therapies and so on. Aubrey de Grey explains that a primary reason people remain in the pro-aging trance is because they are too scared to get their hopes up. However, this all changes as soon as you have drugs that work, even modestly. If you look historically, there is a relevent parallel with infectious diseases such as tuberculosis 100 years ago, as David Wood explains in my interview with him [https://www.youtube.com/watch?v=_6Wz6XxUb0E]. Back then, the population generally accepted the disease as 'natural', 'normal' and an 'act of god' (as they do with aging today) rather than fight it, primarily because they didn't think there was a way to fight it. But as soon as Rober Koch created a vaccine for tuberculosis, people's values shifted immediately an
5Victorel Petrovich13dI have to disagree on 2 points: 1. "When looking at the graph you present, a clear trend emerges: the more complex and larger the organism, the less progress we have made on slowing aging for that organism" -- the trend is not clear. Rather, the worms are an outlier on that graph. Mice are much more complex than flies and killifish (and much closer to humans) and yet, the results achieved are on par. 2. "The fact that there are 130 companies working on the problem with only minor laboratory success in the last decade indicates that the marginal returns to new inputs is low. " -- Most of them have their individual approaches to "the problem" . There are orders of magnitude more variables that affect the health and lifespan, and those companies are trying just a few of them. So, they are just scratching the surface of what it needs to be tried and done. More researchers and companies is definitely what is needed.
2Matthew Barnett12dYou're right about (1). I seemed to have misread the chart, presumably because I was focused on worms. Concerning (2), I don't see how your argument implies that the marginal returns to new resources are high. Can you clarify?
7Victorel Petrovich12dIt depends on what you mean by "new resources". In your text, you wrote "One more researcher, or one more research grant will add little to the rate of progress. " -- and that's what I argued against, above. Simply put, more researchers & companies=> more longevity-influencing factors to be evaluated => higher chance to find ones that work, and work better.
4Chris Hibbert22dThis seems untrue on its face. What we mean by "curing aging" is negligible senescence. The best that has been achieved in mice is doubling their life spans, AFAICT. Extended (human) lifespan would be nice, but it's not the goal.
2Matthew Barnett22dAnd presumably what the cancer researcher meant by curing cancer was something like, "Can reliably remove tumors without them growing back"? Do you have evidence that we have not done this in mice?
3JackH22dI assumed that was a typo and that you meant curing cancer in mice. We have definitely have not yet 'cured aging' in mice, which is called robust mouse rejuvenation (RMR) [https://www.fightaging.org/archives/2014/04/what-is-robust-mouse-rejuvenation-and-why-should-we-care/] . RMR is usually discussed in the context of timelines for longevity escape velocity (LEV), as a relevant milestone on the way to LEV. Aubrey de Grey has put RMR timelines as occuring as soon as 2022 [https://www.reddit.com/r/singularity/comments/au1cdx/aubrey_de_grey_robust_mouse_rejuvenation_rbr/] , and LEV occurring by 2036 [https://www.youtube.com/watch?v=xgXEJqUDYRQ&t=4s].
2Matthew Barnett22dOops, that was a typo. I meant curing cancer. And I overlooked the typo twice! Oops.

This was great. 

Some things that made it great:

  1. It was just in the sweet spot of length. Taking notes, this took me a half hour to read. (I think the ideal is in the 30 minutes to 60 minute range, so doubling the post would have been fine, but more than that would have been overwhelming).
  2. It was written clearly. 
  3. It was full of links that I can use to follow up on the places that I am most interested / confused about.

I would love to read more posts like this one, on a whole variety of topics, and would be glad to help subsidize their production if there was a way to organize that.

5JackH20dThanks for the compliment! Although it only took two days to write, it was the product of several months of thinking about the topic, and putting the pieces together. That said, if you'd like to sponsor me to complete this sequence and/or create more content like this, I would be more than happy to. You can have a look at other content I've created for MindsetHealth.com [https://www.mindsethealth.com/matter/calm-ibs-flare-up]. Please feel free to drop me a line at jtt.harley@gmail.com

I want to consider this post from a decision-making perspective. How can it inform my own future decisions?

First of all, this is the applied goal underlying my graduate-level research. As I continue to learn more about my field of tissue engineering, bioprinting, and regenerative medicine, I might be able to contribute to this growing anti-aging movement. So this post can inform my reading and writing decisions.

Without meaning to be rude, I'm not certain that these sources or this post is credible, simply because I'm only starting to read it and understand it myself. This question is due to my own lack of knowledge, not any issue with the OP. However, it might make a good starting point. It might be valuable to look at the sheer amount of reading it would entail, and the level of mastery I'd like to attain in this domain.

If I wanted to commit a total of 50 hours studying this body of literature, is this post the best place to start? If not, what is? I don't have any better ideas. Perhaps the key question is really where to start within this post.

I think I'm having these credibility and "where to start" concerns because this is a blog post by an anonymous author on LessWrong, rather... (read more)

I completely agree that it is absurd that the kind of content in the OP is not more widely publicized. This was my precise motivation for writing this post. 

Unfortunately, there is no good 'where to start' guide for anti-aging. This is insane, given this is the field looking for solutions to the biggest killer on Earth today. 

The closest approximations to a 'where to start' guide for anti-aging would be:

That said, none of the above communicated all of the ideas that I wished to communicate in the OP in a succinct way. Again, this is precisely why I wrote it.  

It seems to be one of the better introductions out there, as those in touch with field on the longevity subreddit seem to have appreciated my introductory guide, as it's one of the top-rated posts in the past week and has been given 5 awards. As an aside, I'm planning on turning this into a sequence, so if you have ideas for future topics please let me know.

I totally agree regarding funding for 80k equivalent sites. If someone wants to provide ... (read more)

4Yoav Ravid20dI think mentioning your qualifications at the start (or at least the end) of the post would help. i wondered about it myself as i was reading it, and i would have been glad to read them if they were mentioned (instead of, say, feeling like it's bragging).
3JackH20dSure - I've just added that at the bottom. Thanks for the tip.
1David_Kristoffersson19dLow hanging fruit intervention: Create a public guide to that effect on a web site.
5JackH19dCompletely agree - we have this planned on our Oxford Society of Ageing and Longevity website (ageingandlongevity.com). I also plan to write a sequence on LessWrong of perhaps 10-15 posts similar to this one. Feel free to comment if you think there are specific angles you'd like me to focus on (e.g. explaining the science in more detail, discussing common philosophical objections, describing the financing of longevity biotech, etc.).
2Felix Karg13dThank you for writing this, it was very helpful to me. I will read up on a number of links you provided in the post itself and other comments. I'm starting to dabble in Biology since last Semester (Computer Science Bachelors, currently doing Master’s degree) as a minor, some of my current interests are: * Epigenetics Especially related with newly available computational methods and experiments doable with CRISPR-modifications. What are the active areas of research? * Simulation Particularly of biological pathways or other relevant parts. What is commonly simulated? To what degree? * Measuring How easy it is to measure the 'Hallmarks of Aging', and how accurate are their relative predictions? What other measurements would be great to have (soon)? For me, it is not ultimately clear that they are relevant for the field at all, so bear with my selfishness here. I would especially be interested in a (slightly more technical) introduction to the current state of the Art, active areas of research, how it is related to anti-aging research, and how to learn more about each of them. Furthering anti-aging-research/awareness is actually a secondary career goal of mine, the first/current one is figuring out how to consistently raise the sanity waterline in organizations. It might even be possible to fulfill both at one organization, we'll see.
7Victorel Petrovich13dI've been following the anti-aging field for almost 7 years: research news, overview articles, reviews etc. I don't know the author of OP, but I can say that the article he wrote here is as good as it gets (one of the best I've ever read), and, up to date. So are the recommendations he makes for further learning/immersion. I happen to have read many of the articles he cites, and they are all of very good quality. The names he cites (A. De Grey, Sinclair, Barzilai and others) are stars in this field, mentioned in most other anti-aging blogs as well. IMO, the kind of background this author has (not exactly working in aging research, but still within biology and familiar with research in general) is great for writing an overview like this: because it is less biased in terms of a preferred theory and approach for anti-aging - unlike (to various extent) reviews written by a star researcher in the field. Even this author has a preference (SENS) (but perhaps for a good reason, you'll have to judge yourself). So, the pointers given here are all great (just reddit/r/longevity alone will give you as much immersion and leads as you want). Personally, I read/follow some of the sources he recommends, and also follow this blogger https://joshmitteldorf.scienceblog.com [https://joshmitteldorf.scienceblog.com] .
2JackH12dThank-you for the kind words! Stay tuned for more articles like this one coming soon.

I'm preparing for graduate school in tissue engineering via bioprinting. I was motivated by these considerations.

My sense is that ageing is both an evolutionary response to cancer and an entropic inevitability. No matter how much you supplement the body, eventually deleterious mutations will accumulate. The complexity of cellular systems makes them very difficult to improve on.

The strategy I envision is that we'll learn how to manufacture healthy, fresh tissues and organs from the recipient's own cells. While it's very hard to improve on the cell's natural mechanisms, we can harness it in this way to rejuvenate at the level of tissues and organs. People will receive periodic transplants of fresh organs built from their own cells.

(1) Aging is not entropy (second law of thermodynamics). In fact, both young and old individuals are in very high entropic states, and it is not entropy that kills people when they die of aging. Instead, it is the accumulation of biological 'damage' (i.e. hallmarks of aging) described in the original post. If aging was inevitable due to entropy it would be impossible according to the laws of physics for biological organisms such as the hydra and tortoise to display negligible senescence, and for sharks to achieve the 400+ lifespans that they do without any increase in mortality risk. 

(2) Your description of 'deleterious mutations' is accurate - genomic instability which includes DNA damage (as well as chromosomal rearrangement) is one of the 9 hallmarks of aging. But like all of the hallmarks, it is something we can attenuate. There are currently clinical trials for several DNA repair therapies such as nicotinimide mononucleotide (NMN), an NAD+-precursor molecule in Sinclair's lab at Harvard, and nicotinomide riboside (NR) which is being developed by the biotech company Chromadex

For a good primer on genomic instability, I encourage you to read this article from Lifespan... (read more)

4AllAmericanBreakfast22dThanks for writing the OP and for your response, I now see you mentioned this in the original. I’m excited to check your links out. Other commenters mentioned that an issue to anti-aging research in humans is the regulatory barriers. Part of the reason I’m interested in tissue engineering is that it may circumvent that issue to some extent. You can do your research relatively freely on tissue until you’re able to replicate a certain organ, test it on people who need a transplant, and “patch together” an approach to life extension in this way.
3JackH21dGreat to hear you are interested in contributing! I wasn't precisely sure about the anti-aging applications of tissue engineering, so I asked a colleague and this is what he said: So, it definitely seems important!
5Victorel Petrovich13dI think the direction you've chosen, tissue engineering, will be very useful. One important organ for aging to be rejuvenated/replaced is thymus, whose degeneration is a major cause of declining immunity with aging. "No matter how much you supplement the body, eventually deleterious mutations will accumulate." yes, however, in nature, deleterious mutations don't accumulate in all species. Hydra is an example/exception. It replaces its cells at such a fast rate, that this is an important reason why it doesn't accumulate mutations (and other damage) and manages to be biologically immortal. In fact, the direction you've chosen for research would do the same but at the level of tissues/organs, not cells.

It would be great if the mouse results turn out to apply to humans as well, but I have my doubts.  These doubts are based on what I thought were pretty conventional biological assumptions, but that nevertheless don't seem to be addressed in the anti-aging discussions I've seen.

The basic problem is that there's a good reason mice don't live long. Even if they didn't age, the environment in which they live means they are very likely to die in a few years from starvation or predation.  So genes that keep them from aging won't be selected for because of either or both of two reasons:  (1) The selective advantage of not aging, when you're likely to die young anyway, isn't enough to overcome random mutation that undoes the anti-aging genes. (2) The advantage of not aging comes at some (possibly rather small) cost in terms of increased likelihood of death from predation or starvation, or decreased fecundity early in life. (For instance, it might have an energy/food cost, or might come with decreased physical performance, such as in running speed.)

Humans live in a different environment, in which slower aging is more advantageous. And indeed humans age much slower than mice, ... (read more)

3JackH21dYou are correct that interventions in mice do not always translate well to humans. Fortunately, several human trials have already shown that aging can be reversed [https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028]. Time will tell how many of the current anti-aging approaches that have worked in mice [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/] will translate to humans. This comment doesn't make a lot of sense to me since mice used in the lab for lifespan studies are not subject to evolution today - rather, specific strains used for different kinds of experiments are purchased from specialized laboratories [https://www.jax.org/jax-mice-and-services/find-and-order-jax-mice] , where they are selectively bred. I don't agree with this. Senescent cells (one of the 9 hallmarks of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/]) for example accumulate both in humans [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/#:~:text=Cellular%20senescence%20is%20thought%20to,including%20stem%20and%20progenitor%20cells.] and mice [https://www.nih.gov/news-events/nih-research-matters/eliminating-senescent-cells-extends-healthy-life-mice] with older age, and contribute to age-related tissue and organ dysfunction [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214092/#:~:text=Cellular%20senescence%20is%20thought%20to,including%20stem%20and%20progenitor%20cells.] in both. Senescent cells by definition are apoptosis-resistant [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4253488/], meaning they are resisting the mechanisms (found in both mice and humans) to remove them. Hence, senolytic drugs extend lifespan in mice [https://www.nih.gov/news-events/nih-research-matters/eliminating-senescent-cells-extends-healthy-life-mice] and probably humans [https://www.lifespan.io/news/human-pilot-study-results-for-senolytics-published/] by removing these cells, since the machinery in the body is unable to. Following on from my previous comment, your

[F]ew members of [LessWrong] seem to be aware of the current state of the anti-aging field, and how close we are to developing effective anti-aging therapies. As a result, there is a much greater (and in my opinion, irrational) overemphasis on the Plan B of cryonics for life extension, rather than Plan A of solving aging. Both are important, but the latter is under-emphasised despite being a potentially more feasible strategy for life extension given the potentially high probability that cryonics will not work.

I think there is a good reason for there being more focus on cryonics than solving aging on LessWrong. Cryonics is a service anyone with the means can purchase right now, whereas there is barely anything anyone can do to slow their aging (modulo getting young blood transfusion and perhaps taking a few drugs, neither of which work that well).

If you are a billionaire, or very knowledgeable about biology, you might be able to contribute somewhat to anti-aging research — but only a very small fraction of the population is either of those things, whereas pretty much anyone that can get life insurance in the US can get cryopreserved.

I agree that the LessWrong community can have a positive impact on the cryonics field by signing up for cryonics and direct more capital in to this extremely under-funded field. Cryonics is especially relevant for people older than 40 today who are much less likely to make it to longevity escape velocity.

However, I disagree that (1) there is barely anything people can do now to slow their aging and (2) there is barely anything that the average person can do to support the research and development of anti-aging therapies. I plan to write a separate post covering these points, but I'll provide a few thoughts here.

Regarding (1), there are a multitude of actions you can take now to slow your aging and risk of age-related diseases (disclaimer: NOT a substitute for medical advice):

Non-pharmacological:

... (read more)
5Matthew Barnett22dThe personal strategies for slowing aging are interesting, but I was under the impression that your post's primary thesis was that we should give money to, work for, and volunteer for anti-aging organizations. It's difficult to see how doing any of that would personally make me live longer, unless we're assuming unrealistic marginal returns to more effort. In other words, it's unclear why you're comparing anti-aging and cryonics in the way you described. In the case of cryonics, people are looking for a selfish return. In the case of funding anti-aging, people are looking for an altruistic return. A more apt comparison would be about prioritizing cryonics vs. personal anti-aging strategies, but your main post didn't discuss personal anti-aging strategies.
7JackH21dBoth are important. Anti-aging is unique in the following way: since all of us are slowly dying of aging, it's in our best interest to want the field progress for selfish reasons, but also our altruistic interest for society to solve aging as soon as possible, as this saves millions or billions of human life years. On a personal level, maximising the probability of reaching longevity escape velocity [https://en.wikipedia.org/wiki/Longevity_escape_velocity] is a min/max problem with two important variables: (1) maximising personal lifespan, by adopting personal longevity strategies (2) minimising the time until society reaches longevity escape velocity by helping to progress the longevity field. You can think of it as a 'race against time' - to live forever (or at least, a very long time) one has to live in the subset of worlds which represents the intersection of society achieving longevity escape velocity, and one living long enough to make the cut, to avoid being among the last generations to die [https://www.fightaging.org/archives/2013/09/the-last-generation-to-die/]. Personal longevity strategies are important, since a few years of additional life from longevity strategies could be the difference as to whether one makes it to reach longevity escape velocity or not. I suspect that many baby boomers may, unfortunately, miss the cut, but many Millenials and Gen Z's could make it, particularly if they are proactive with longevity strategies. Progressing the field is also important, as living to 150 with personal longevity strategies doesn't mean much if you fall 5 years short of reaching LEV because timelines were too long, for example. Now, as to which is more important - personal longevity strategies or progressing the field - it's unclear. Aubrey de Grey in his recent interview with me [https://www.youtube.com/watch?v=xgXEJqUDYRQ&t=4s]stated that the latter is much more important, since future therapies will vastly improve healthspan more than anything we ca
1deskglass13dIf Brunemeier's PDF's is something you can share, I'd like to read it.
2JackH13dHere's some of the important stuff (not medical advice, obviously): Daily multivitamin Omega 3 fatty acids (EPA/DHA) Magnesium citrate Turmeric (curcumin) Resveratrol / pterostilbene Metformin / berberine Apigenin Quercetin NR (nicotinamide riboside) EGCG (green or white tea) Ocimum sanctum (Tulsi) Bacopa monnieri (standardized 20% bacosides) Gotu Kola (Centella asiatica) Gingko biloba B12 – many people are deficient Vitamin D (get blood tested to optimize, ideally 30 min/day full sun, 2000 IU) Vitamin C (megadose, 5 g / day +, spread throughout the day) Piracetam + Choline Uridine Acetylcarnitine + N-acetyl cysteine Glycine Supergreen/superfruit blend*: “Blender Culture” .
1Synaptic19dI strongly support anti-aging research. I'm not clear on what your criticism is of cryonics. Perhaps I missed where you explained why you think that cryonics will not work? For example, where in the Drake equation does your probability differ from Steve Harris's or Mike Perry's? Also, you point out the large number of organizations and companies involved in aging research. Surely the fact that there are way fewer in cryonics means that it is has merit from an underfunding perspective?
1JackH19dThe estimates of Harris and Perry that cryonics doesn't work range from 23% to 99.8% - which are potentially quite high (as I phrased it in the OP). Cryonics might work, but there's a potentially very good chance that it doesn't. I agree that cryonics is underfunded even more than aging research. It seems likely that an increase in funding to cryonics could increase the probability that cryonics works, by improving the chance of success of the following variables: * Favorable conditions for suspension * Suspension preserves enough information * Mishap-free storage * Nanotechnology is perfected * Cryonic revival is "cheap enough" At the very least, it would help to reduce the uncertainty regarding some of the parameters, providing as a clearer picture of the feasibility of cryonics. However, several of the parameters would be likely to be unaffected by increased funding: * Materialism is correct * Identity encoded in structure * Sufficient social stability * Cryonics is continuously legal * Nanotechnology is physically possible * Cryonic revival is permitted Ideally, both cryonics and anti-aging would receive more funding. The intention of my post was not to encourage reductions in funding into cryonics; rather, to increase awareness among LessWrongers readers about anti-aging.
1Synaptic18dOn the contrary, I very much expect that more funding would help with these factors. The success of cryonics is limited by sociopolitical factors, and the more people who have buy-in, the more likely people are to be protected when in long-term cryopreservation. This is an admirable goal. =)
1JackH18dYeah, that seems likely. Certainly 'the social problem' (which combines several of the parameters) in general will reduce in likelihood the more funding cryonics receives.

Random question: Why is there such a large difference between the life extension results for mice vs. for rats. Naively, they seem like they're pretty similar. 

Are we trying different kinds of treatments on one than the other for some reason, or is it just much harder to intervene on rat life-spans?

2johnswentworth9dMy understanding is that the usual lab mouse breeds are highly inbred, resulting in high levels of cancer. That makes is "easier", in some sense, to extend their lifespans - especially by interventions which trade off cancer risk against other age-related deterioration. For instance, there are ways to make cells more sensitive to DNA damage, so they undergo senescence at lower damage levels. This can decrease cancer risk, at the cost of accelerating other age-related degeneration.

For personal longevity strategies, I recommend talks by Dr Rhonda Patrick, Dave Asprey and Dr Peter Attia. 

Dave Asprey is a person who claimed to increase their IQ by 40 points without engaging in any effort to measuring his IQ by taking the best results found in p-hacked trials for interventions and adding them up. I think that was even before he went into business as a supplement salesman.  

More recently he argued that he believes in reincarnation because it helps him to lower his stress levels. 

He references a lot of research, but I don't... (read more)

7JackH21dDave Asprey's book, Superhuman is pretty good - it explains the hallmarks of aging in simple terms and provides generally good advice for limiting the damage associated with the hallmarks. He draws upon a lot of scientific literature, and has over 400 academic references. Asprey does a good job synthesising the research into practical steps a person can take to lower their rate of biological aging - something that most of the researchers in the field don't have the time to do. A few things are a bit wacky, but in general I'd say 95% of the advice he says is pretty good, and the other 5% won't do any harm. Dave Asprey is a pioneer of the longevity biohacking community, and runs a supplement company called bulletproof. But, if you don't like his advice, then you can look towards Rhonda and Attia. Dr Rhonda Patrick has a PhD in cell biology and is extremely knowledgeable about aging and longevity - just watch her interviews with David Sinclair [https://www.youtube.com/watch?v=5DtWqzalEnc], Valter Longo [https://www.youtube.com/watch?v=d6PyyatqJSE] or Steve Horvath [https://www.youtube.com/watch?v=A_aaBKubJnA] - all big names in the field. She talks to them on the same level since she knows the literature very well. Dr Peter Attia is an MD who is also very clued up on the aging field too, and on his podcast has also interviewed many big names such as David Sinclair [https://peterattiamd.com/davidsinclair2/] and Nir Barzilai [https://peterattiamd.com/joanmannick-nirbarzilai/]. I recommend this talk of his as an introduction to some important concepts in aging. David Sinclair's book Lifespan [https://lifespanbook.com/]is also the gold standard for personal anti-aging strategies, which are summarised here. [https://naturallystrong.me/david-sinclair/]

Here's a Peter McCluskey review on "age later" from back in October.

Thanks for an amazing post, Jack!

I think it's worth mentioning that damage accumulation as the root cause is not the consensus view anymore.

To quote Josh Mitteldorf, there are three views:

  1. (from the “programmed” school) Aging is programmed via epigenetics. The body downregulates repair mechanisms as we get older, while upregulating apoptosis and inflammation to such an extent that they are causes of significant damage.
  2. (from the “damage” school) The body accumulates damage as we get older. The body tries to rescue itself from the damage by upregulating repai
... (read more)
3JackH21dHi Alexey, So, having talked to a number of people in longevity biotech, I'm skeptical as to whether view (1) i.e. Sinclair's 'information theory of aging' which posits epigenetic aging is the master regulator for the other hallmarks is accurate, and that cellular reprogramming alone is sufficient to slow aging. I think the information theory of aging [https://hplus.club/blog/a-summary-of-david-sinclairs-information-theory-of-aging/#:~:text=Regulating%20gene%20expression%20is%20the,female%20in%20the%20example%20here).] is good PR for the field, [https://www.youtube.com/watch?v=_G2gy1zBilA] but I don't think it's entirely correct. Still, the next 5 years of research will provide more clarity as to the relationship between epigenetic alterations and the other hallmarks of aging. I hope (1) is true although from the data I've seen and people I've spoken to behind the scenes, I don't think it's likely that cellular reprogramming alone will be enough. I think the hallmarks develop to some extent independently, even though there is some level of cross-talk between them, and will have to be individually addressed.
1Alexey Lapitsky21dVery curious to hear a bit more about why you are skeptical about epigenetics and information theory of aging as the primary cause. But I completely agree that it's not the only cause! "Being sufficient to slow aging" is a pretty low bar, I have virtually no doubt that reprogramming will slow aging (it already has been done experimentally with mice).
4JackH21dI don't see a lot of evidence for the information aging theory in the literature, and most geroscientists don't seem to think that epigenetics is the master regulator of the other hallmarks. This isn't to say it's not true, just that there's insufficient evidence at this point. Sinclair discusses all of the hallmarks, but focuses on epigenetics as the most important - which is incidentally the one he studies. Bear in mind as an academic this is something are incetivised to do - to tell a narrative that fits their research agenda, to attract funding. Looking at the field as a whole, there is consensus about the hallmarks but not so much consensus about the information aging theory, and in fact I don't know of any other major geroscience researchers who have endorsed the information theory of aging. It's too early to say that he's incorrect, but the theory seems unlikely from my reading.
1Alexey Lapitsky21dInteresting, thanks! My thinking is that: 1. Methylation increases with age and predicts biological age 2. Methylation affects protein synthesis in a semi-random way Those points mean that epigenetics at least partially causes all hallmarks dependent on protein synthesis (loss of proteostasis, intercellular communication, etc). Meaning that epigenetics is at least partially upstream of at least a few hallmarks. Not sure what being correct about information theory of aging would exactly mean or what other evidence to expect. Intuitively it feels that our efforts should focus upstream and that there are more low hanging fruits in epigenetics than in most of the other hallmarks.
1JackH21dThat seems plausible! The only thing I'll say is that from what I've heard, epigenetic reprogramming in vivo may be particularly challenging in many tissues in the body. Therefore, I suspect mTOR inhibitors and senolytics may be lower hanging fruit for anti-aging therapies approved first.

Hi, I was a talk at a conference, in 2019, that mentioned that many new breakthroughs in cancer research were down to improvements in the accessibility of data science, and large scale computing.

As a Software Engineer, is there any way I can contribute these type of skills towards longevity research? The only avenue I could find was to get a job at Calico, but realistically, I'm half a world away in Ireland.

5Victorel Petrovich12dJust of the top of my mind: an example lab that makes (relatively heavy) use of computational approaches is that of J.P. de Magalhaes (U.of Liverpool, so not too far from yourself). More generally, I believe many labs nowadays could use the help of a software engineer. You could read more on aging research (this article has great links, AFAICT), choose a direction, a lab, and ask them if you can help them. I might to the same, one day.
4JackH21dHi Thomas, Great to hear you are interested in contributing to the field! You can have a look at LongevityList.com [https://longevitylist.com/] and see if there's anything on there. It's a new project so I'm not sure how regularly it's updated. Alternatively, you could join the Longevity Subreddit [https://www.reddit.com/r/longevity/]and the Lifespan Discord [https://discord.gg/4gNG9q4] server and ask there, as there are many people involved in the field there willing to help. Often, people like yourself will ask about job opportunities and get connected with opportunities. Hope that helps!

There is a problem with most anti-aging interventions: long expected duration of human trials, as results and lack of side effects will be obvious only decades after the start oа such trials. Without trials, FDA will never approve such therapies. 

However, there is a way to increase the speed of trials using biomarkers of aging - or testing of already known to be safe interventions, like vitamin D. But biomarkers need to be calibrated and safe interventions provide only small effects on aging. Thus, it looks like some way to accelerate trials is needed if we want radical solution to aging to 2030. What could it be?

7JackH22dYes, we need improved biomarkers of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5473407/]. Once we have biomarkers that are accurate enough to detect changes in aging or anti-aging over the course of months, it will be much easier to obtain high-quality data for prospective anti-aging compounds. Another solution that aging researchers have discussed is developing frameworks for decentralized clinical trials [https://www.sciencedirect.com/science/article/pii/S2451865418300358] that could bypass institutional approval but still produce credible results. There also needs to be a paradigm shift in society, biomedical research, and regulatory bodies like the FDA to recognise and classify aging as a disease [https://www.lifespan.io/news/not-classing-aging-as-a-disease-is-not-a-major-problem/] . Open science [https://en.wikipedia.org/wiki/Open_science] which aims to make all science accessible to everyone, whether amateur or professional, is would also help to accelerate the rate of research.
2pjeby22dAny pointers on what to search to find more info on this from actual research? I wasn't aware that vitamin D was considered to have anti-aging properties, or that there was much consensus on its safety.
5JackH22dFor a good summary video on vitamin D and aging, I recommend this [https://www.youtube.com/watch?v=uc815fQn8iY&t=143s]. For academic papers and other articles, I recommend this [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689451/], this [http://blog.wellnessfx.com/2013/08/14/the-vitamin-d-sweet-spot-and-its-relationship-to-aging/] and this [https://www.sciencedaily.com/releases/2012/11/121105130355.htm]. For information on personal longevity strategies, I recommend the following: - Watching videos by Dr Rhonda Patrick [https://www.youtube.com/user/FoundMyFitness], Dr Peter Attia [https://www.youtube.com/watch?v=vDFxdkck354&t=2427s] and Dave Asprey [https://www.youtube.com/watch?v=z1tO6h567oc] - Joining Facebook biohacking groups such as this [https://www.facebook.com/groups/493331218172184], and this. [https://www.facebook.com/groups/endagingnow] - Joining the Lifespan discord server [https://discord.com/invite/4gNG9q4] and reading comments on the 'personal longevity strategies' channel.
4avturchin22dIt is safe enough to be sold OTC, and there are some research [https://www.sciencedaily.com/releases/2016/10/161025125102.htm] which connects with life extension effects. The real problem is that we don't have human tests of its effects on longevity, despite its widespread use. The first study like this will be TAME, which will explore life extension properties of metformin. There are several reasons why such studies are difficult to perform. Firstly, they are costly, but known safe things are non-patentable. Secondly, they need to be very long., and long human studies are especially costly.
1Yoav Ravid22dAnother option is to advocate for emergency authorization for old people.
2avturchin22dUnfortunately, it seems that most intervention works before aging actually developed, so we need to give them to younger people, at least before 50.
4JackH22dThis is not true. Aging doesn't develop, rather, it is an ongoing process of damage accumulation (i.e. hallmarks of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/]) that occurs as a by-product of metabolism, explained in the original post. Aging occurs in both young and old people, although the rate of aging accelerates as diseases of aging develop [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890129/]. Reversing the damage associated with the hallmarks of aging at any chronological/biological age is likely to improve their phenotype and expected longevity. The more advanced the anti-aging technologies become, the better equipped we will be to reverse large amounts of damage associated with advanced age. That said, there is no reason to think that there is a cliff after which aging cannot be reversed.
3avturchin22dThat is true for therapies which work on damage (SENS). But if we see aging as a process which creates the damages, than it is reasonable to stop it on early age. Also, I've seen a recent article "Longevity‐related molecular pathways are subject to midlife “switch” in humans" which implies that many interventions should happen early in life. Thanks for great post!
4JackH21dEvidence in mice studies does indicate that earlier therapies (for example of senolytics) do facilitate greater life extension. However, with better anti-aging technologies the 'switch' (from the paper you refer to [https://www.researchgate.net/deref/http%3A%2F%2Fdx.doi.org%2F10.1111%2Facel.12970] ) could theoretically be reversed, as there's no biological law that would prevent restoring a phenotypically older individual back to a more youthful state.
1Yoav Ravid21dI see. in that case perhaps we would need emergency authorization for anyone who needs it to stay within escape velocity timeline. though that definition is too complex for me to see a scenario where FDA approves it (at least not without massive pressure).
3JackH21dYes, I hope regulators will give older individuals who are soon to die of aging the option to have access to more radical life-extension therapies.

Promoted to curated: I've been meaning to follow up on the state of anti-aging work for a while, and this was really a quite good overview. I also know of a number of other people who found it useful. Thank you for your work when compiling this overview!

1JackH9dThank you very much, I appreciate it. This is only a short introduction to the field, and I plan to write several follow-up articles in the near future to create a larger sequence (covering: aging and COVID-19, the ethical arguments for/against anti-aging, aging and cancer, and more anti-aging therapy approaches).

In part 1 is this error:

"This equates to 37 million people - a population the size of Canada - dying per day of aging."

Fix: change "day" to "year"

3JackH21dFixed, thanks!

Regarding cryonics not working: this depends on your definition of 'working'.  Let me describe the problem succinctly.

Assume at some future date you can build a 'brain box'.  This is a machine, using some combination of hardware and dedicated circuitry, that is capable of modeling any human brain that nature could build.  It likely does this by simulating each synapse as a floating voltage, modulated by various coefficients (floating point weights) when an incoming pulse arrives.  

Well, you can choose randomly the weights, and assuming ... (read more)

4JackH22dHi Gerald, In the original article, I linked to Alcor's calculation of the probability that cryonics works [https://www.alcor.org/library/will-cryonics-work/]. It ranges from 0.2-77% [https://www.alcor.org/library/will-cryonics-work/] and this calculation is based on the 14 variables below: 1) Materialism is correct 2) Identity encoded in structure 3) Favorable conditions for suspension 4) Suspension preserves enough information 5) Mishap-free storage 6) Cryonics organization survives 7) Sufficient social stability 8) Cryonics is continuously legal 9) Nanotechnology is physically possible 10) Nanotechnology is perfected 11) Nanotechnology is non-catastrophic 12) Cryonic revival is "cheap enough" 13) Cryonic revival is permitted 14) The social problem Depending on your probabilities for these variables, the estimation of the overall probability that cryonics will work overall will vary.
2magfrump21dEven 0.2% seems quite optimistic to me. Without going into detail, anything from 3-8 seems like it could be 10% or lower and 12-14 seem nearly impossible to estimate. I wouldn't be surprised to find my personal estimate below one in a million.
3JackH21dYeah. For your interest, here are the calculations from Alcor: Steve Harris, MD: 1) Materialism is correct: 0.95-0.99 2) Identity encoded in structure: 0.95-0.99 3) Favorable conditions for suspension: 0.75-0.95 4) Suspension preserves enough information: 0.50-0.90 5) Mishap-free storage: 0.95-0.99 6) Cryonics organization survives: 0.20-0.60 7) Sufficient social stability: 0.70-0.90 8) Cryonics is continuously legal: 0.70-0.90 9) Nanotechnology is physically possible: 0.90-0.98 10) Nanotechnology is perfected: 0.95-0.98 11) Nanotechnology is non-catastrophic: 0.20-0.50 12) Cryonic revival is "cheap enough": 0.85-0.95 13) Cryonic revival is permitted: 0.50-0.80 The social problem is non-catastrophic: 0.008-0.18 Technologically, will cryonics work? 0.29-0.81 Overall, will it work? 0.002-0.15 That is, a 0.2-15% probability that cyronics works overall. Mike Perry, PhD: Note: his calculation lumps 7 of the 13 parameters as 'the social problem' which he calls condition n. 1) Materialism is correct 1.00-1.00 2) Identity encoded in structure: 1.00-1.00 3) Favorable conditions for suspension: 0.75-0.95 4) Suspension preserves enough information: 0.50-0.90 5) Mishap-free storage: 0.90-0.99 6) Cryonics organization survives: n-n 7) Sufficient social stability n-n 8) Cryonics is continuously legal n-n 9) Nanotechnology is physically possible 1-1 10) Nanotechnology is perfected n-n 11) Nanotechnology is non-catastrophic n-n 12) Cryonic revival is "cheap enough" n-n 13) Cryonic revival is permitted n-n The social problem is non-catastrophic: 0.39-0.86 Technologically, will it work? 0.34-0.89 Overall, will it work? 0.13-0.77 That is, a 13-77% probability that cyronics works overall.
2magfrump21dYeah I think my main disagreements are 4 and 5. Given stories I've heard about cryonics orgs, I'd put 10-50% on 5. Given my impression of neuroscience, I'd put 4 at 25-75%. Given that I'm more pessimistic in general, I'd put an addition 2x penalty on my skepticism of their other guesses. That puts me around 0.01%-20% spread, or one in ten thousand lower bound, which is better than I expected. If I was convinced that a cryo org was actually a responsible business that would be enough for me to try to make it happen.
1JackH20dYes - it's hard to perform the calculations and end up with a high probability that cryonics works. I think cryonics overall is much less feasible than many Less Wrongers tend to assume. Overall, I think anti-aging has a much higher chance of working to keep us alive much longer than cryonics does.

Do we understand why cats live longer than dogs?

Minor correction: the metformin trial study (TAME) is not currently underway; they are still waiting for the FDA to designate aging as an "indication" to be treated (and also raising funding).

 

Good writeup, though, thanks!

4ChristianKl22dIt got the necessary approval in 2015 and in 2019 a rich private individual seems to have given them the missing 40$ million to run the trial: https://www.longevity.technology/worlds-first-anti-aging-trial-gets-green-light/ [https://www.longevity.technology/worlds-first-anti-aging-trial-gets-green-light/] and the plan was to start the trial at the end of 2019. It might very well be running currently. Maybe someone else has more info?
1T3t21dOh, interesting, thanks for the correction! I was just going by their website (linked in the OP), which may not have been updated since 2015(?!).

Science fiction author and physicist David Brin has pointed out a theoretical reason why we might expect anti-aging therapies that work in mice to fail in humans: the human lifespan is already a ridiculous outlier. Life spans vary with size, metabolism, and other factors, but one thing tends to hold constant: most mammals have a lifetime of about one billion heartbeats. Humans get a whopping 2.5 times that. An intervention would have to more than double a mouse's lifespan just to catch up with whatever it is that evolution has already done to humans - if there are any simple mechanisms that can cause a mammal's body to increase its lifespan, humans are probably already pushing them to their limits.

Besides donating money to SENS, is there any way for people with money to help speed up this research? Specifically, are there companies that one can invest in to help this research? Say if you're in charge of a lot of investment money (maybe you're a fund manager or ethical investment advisor or something) and want to make investments that make the world a better place. Anti-aging sounds like it would be a great place to invest some of the financial capital available. How would one do that? 

Fellow humans, do forgive my newbieness, but I am surprised this following study has not been mentioned: 
 - https://www.aging-us.com/article/202188/text
I speak no chemics, so I might've lost something midway of the presentation. Yet, since I have celebrated the aforementioned article as my most cherished 2020 article, I've guessed the chance of it cherishing someone's day upward was worthy of the hereby mentioning. I shall read replies probably: in case I take time to do so, one may consider oneself thanked for the reply, in advance.

1JackH7dI did not include the Tel Aviv/HBOT study [https://www.aging-us.com/article/202188/text] since it is not considered a promising approach to anti-aging by most researchers in the field. The conclusions of the study are potentially misleading, due to the highly improbable senolytic effect of oxygen therapy [https://www.lifespan.io/news/media-circus-surrounds-hyperbaric-oxygen-study/]. In my recent interview with Dr Aubrey de Grey, I asked him about this same study (timestamp: 40:30) [https://youtu.be/xgXEJqUDYRQ?t=2437], and he said that it was enormously over-hyped. I encourage you to read this article, which explains the media circus around the study, and critiques the science: https://www.lifespan.io/news/media-circus-surrounds-hyperbaric-oxygen-study/ [https://www.lifespan.io/news/media-circus-surrounds-hyperbaric-oxygen-study/]

Love this article.

After reading the The Fable of the Dragon-Tyrant a few years ago after my father died, I went into a deep dive on this and ended up making a calculator, comparing the impact of eliminating various causes of death on average / median lifespan. It's very simplistic, but I found it interesting to use to illustrate how ageing contributes to death:

http://life.analogmantra.com/ 

2jmh17dVery interesting. Assuming we eliminated everything but accidental causes looks like we should live to about 120+ years. I think Sinclair had said that was the expected lifespan as well. Taking the tool at face value, it seem that both personally and socially effort focused on circulatory diseases should give the biggest bang for the buck. Then again I didn't run through different cases of combination so...
2CronoDAS3dIf the actuarial statistics I've read are accurate, about 1 in 1000 18 year old men in the US die before their 19th birthday. If the chance of dying each year stayed perfectly flat, life expectancy would be about 1000 years...
1AM13dTrue, circulatory diseases would be a big win, but do you think the marginal buck there is likely to do as much as a marginal buck focused on aging giving the amount of funding allocated to each? If we add the R&D budgets focused on circulatory diseases to the treatment cost of circulatory diseases (potential profit pool for pharma companies), my intuition says that the number would be ~20-100x the total amount of funding to aging-stopping or -reversing technology. What do you think the ratio would be?
2JackH19dReally love the app, great work! Just a bug I found (I think it's a bug?) - if I untick all the boxes, the median age of death goes to 0.
1AM19dDefinitely a bug! It was my first and only foray into D3.js so there are a lot of bad states you can get into fairly easily. Might rebuild it in something else one day.
2JackH19dI think it would be worth rebuilding if you have time. If you do, make sure to share it on Longevity Subreddit [https://www.reddit.com/r/longevity/]. You will get a lot of interest in it there.

Mike Lustgarten's work should be added in the reference sections:

book: https://michaellustgarten.com/2016/11/18/microbial-burden-a-major-cause-of-aging-and-age-related-disease/
website: https://michaellustgarten.com/
twitter: https://twitter.com/mike_lustgarten

The evidence is promising that in the next 5-10 years, we will start seeing robust evidence that aging can be therapeutically slowed or reversed in humans

 

Are you willing to bet on this? If so, how much?

4JackH20dDefinitely. There are over 50 therapies in clinical trials for aging today [https://www.lifespan.io/road-maps/the-rejuvenation-roadmap/], addressing various components of cellular aging (i.e. all 9 hallmarks), and many have shown life extension effects in mice, and amelioration of the decline associated with age-related conditions in humans. I'm convinced some of these therapies, when administered from mid-life onwards, would extend human lifespan by 5 years or more. Especially if their delivery is personalised [https://en.wikipedia.org/wiki/Personalized_medicine#:~:text=Personalized%20medicine%2C%20also%20referred%20to,response%20or%20risk%20of%20disease.] and biomarker [https://en.wikipedia.org/wiki/Biomarkers_of_aging#:~:text=Biomarkers%20of%20aging%20are%20biomarkers,different%20from%20the%20chronological%20age.] -optimised. I expect some combination of these therapies, in tandem, to extend healthy human lifespan by 10 years or more. The challenge lies in proving this within the next 10 years, since it would take up to 50 years to run a full-length human lifespan study. So it comes down to how we define robust evidence that aging can be slowed therapeutically. For this, we need accurate biomarkers of aging [https://pubmed.ncbi.nlm.nih.gov/32084299/], and unfortunately, we don't have the best aging biomarkers yet. On the other hand, one could argue we already have robust evidence that aging can be slowed from thymic rejuvenation (using GH+DHEA+Metformin) demonstrated in 2019 to reverse biological age by 2.5 years with 1 year of treatment [https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13028]. However, the extent to which this can be considered robust evidence that aging can be slowed depends on who you are talking to in the field, and their familiarity with aging clocks. If we are using epigenetic aging as the measurement, I'd bet all the money in my bank that at least one additional pharmacological compound will be shown to slow or reverse epigenetic a
7ChristianKl20dIt might be worthwhile to formulate some of those predictions into Metaculus questions.
1JackH20dIt's a good idea. There is already one on essentially this topic: Will there be a culturally significant development in aging research by 2030? [https://www.metaculus.com/questions/3458/will-there-be-a-culturally-significant-development-in-aging-research-by-2030/] The median is 65% so it seems most people (at least, out of those who have responded here) seem to agree with my 10-year timeline for important discoveries. And this is another one anti-aging-related: Will a senolytic therapy be approved for commercial sale by the United States Food and Drug Administration before January 1 2030? [https://www.metaculus.com/questions/1621/will-a-senolytic-therapy-be-approved-for-commercial-sale-by-the-united-states-food-and-drug-administration-before-january-1-2030/] The median is 58% for this one. I haven't used Metaculus before and I don't know what value I could bring by signing up for Metaculus and adding new questions. I intuit that my time would be better spent progressing the research forward so the optimistic predictions actually occur, rather than endless forecasting. That said, I don't know much about how Metaculus works. If you think it's a good platform for outreach and educating people about the field then I would consider it. Or, if you think there are certain kinds of questions I should ask (e.g. regarding the success of individual anti-aging approaches, maybe?). Let me know.
2ChristianKl18dWhen it comes to good long-term strategy and investment of resources understanding how the future likely looks like can be helpful. The act of writing a good Metaculus question is about operationalizing thinking about the future. A question on the likelihood that research that's spun out of SENS leads to an FDA approved drug might be useful for outreach. Both getting people to seriously think about the likelihood is useful and also to be able to use it when talking about the value of donating to SENS to rationalists. For people outside the field it's hard to evaluate the value of SENS by reading papers on their website. On the other hand likelihood to lead to a FDA approved drug is a metric that's a lot easier to think about. Maybe you also have a better idea then likelihood of a FDA approved drug for your vision of the effect that SENS will have. It seems to me like your thoughts about the importance of biomarkers of aging could also form the basis for questions. Thinking about good questions is about thinking what kind of events will be important in the next 20 years and building clarity about that is useful.
1JackH16dThat seems like it could be a good idea. A few more questions though: How would writing the question help to convince people? Would it not only be convincing in 5-10 years' time if some of the predictions turn out to be accurate? Or, do you think if consensus on a Metaculus question that prediction X will occur is in and of itself convincing for rationalists? I'm still a little uncertain about the practical benefit of writing questions, in helping to advance the technologies.
2NunoSempere20dThoughtful answer, thanks

When it comes to the idea of massively improving healthcare outcomes there seem to be two strategies. One is to focus on antiaging. The other is to focus on increasing our research capability by improving the tools we have available.

When Zuckerberg went out and interviewed heatlh care experts it seems they convinced him that tool building is more promising then object level research. 

How strongly do you believe object level research on antiaging to be better then tool building? What's your argument for it?

7JackH21dDeveloping platform technologies [https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/how-new-biomolecular-platforms-and-digital-technologies-are-changing-r-and-d#] is important in pharma and biotech, and that's happening. But the limiting factor seems to be testing anti-aging drugs, and developing better biomarkers. There is no shortage of potential anti-aging therapies - there are hundreds waiting to be tested. The limiting factors are funding and researchers. We need more laboratories working on testing new therapies for anti-aging.
5jmh21dI'm just wondering about the problems with funding and researchers. One would think that plenty of money is actual around but it's more about both awareness and some belief that a tangible return to the investors would be likely. That seems like it might be more a problem of asymmetric information as it were -- or perhaps a bit of "language" between the groups. What's your sense there? For research is there any structure that might work a bit like various gig-econcomy sites. Basically forums that work as an infrastructure to allow a wide audience of those capable of research/analysis to form quick teams to tackle a problem. Or perhaps just do some of the initial leg work to see if some line of thinking is actually going somewhere? I have the suspicion that perhaps a lot of the effort here might be less about lab work and more about digging though the results (but that may well be completely wrong). If both the above are kind of right and some type of open infrastructure that brings both together might be useful -- though also suspect there must be a bunch of incubator type structures already in place.
2JackH20dYou're 100% spot on here. 'Curing aging' and 'longevity' aren't common ideas in biomedical research, but 'curing cancer', 'curing Alzheimer's' and 'curing heart disease' are. This is unfortunate given aging is driving all of these conditions. It can sometimes be frustrating being in the longevity field, because researchers in other fields are incentivised to remain in their silos in which the core premises (e.g. curing cancer is good and effective) are treated as dogma, rather than see the bigger picture and work on solving the problem in more efficient ways. Once you suggest that slowing aging might be a more effective approach to extending healthy human lifespan, many researchers find it difficult to engage in the conversation. This is especially the case since education into the biology of aging is extremely poor in most biomedical and medical programs. Even in my case, I went through 5 years of tertiary education without learning the information in the OP. This information I gathered through speaking to experts in the field, reading books such as Lifespan, reading blogs like Lifespan.io and FightAging.org, reading thousands of papers on this topic and attending aging conferences. Still to this day, there are unfortunately very few channels educating people on the hallmarks of aging and the connection between these and the diseases of aging. Most cancer researchers I spoke to know very little about the hallmarks of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/], for example, and the connection between the hallmarks and disease. This is because their work focuses on solving the problem of cancer once it arises, rather than solving it in advance by curing aging. All of their incentives (grant funding, publication opportunities) are towards trying to cure cancer, rather than trying to extend healthy human lifespan (and delay the onset of cancer, potentially for hundreds of years) by slowing or reversing aging. This is unfortunate since, as I outlin
3ChristianKl21dWhile it's happening it's worth pointing out that the article you linked says "Given that pharma companies depend on innovation, science, and research and development, it may seem counterintuitive that they lag behind the digital curve. In McKinsey’s ongoing survey to measure companies’ “Digital Quotient,” the pharmaceutical industry ranks in the bottom third of industries measured." It doesn't happen as fast as it would be desirable. It's my impression that SENS focuses on doing basic research and not testing anti-aging drug candidates. If that's how you see the current bottleneck why recommend SENS and Lifespan.io over Lifespan Research Institute which actually focuses on testing anti-aging drugs? It could be that the problem of biomarkers is about doing a lot of measurement with our existing tools and looking for correlations. It could also be that we need tools that measure certain biometrics more accurately and cheaper then we currently can to progress. The position that we already have all the necessary measurement tools seems to me optimistic. If you hold it, why do you hold it?
2JackH20dI encourage you to read the full article, not just the first paragraph. Specifically: SENS fund basic research that leads to new approaches to anti-aging drug development. Here is a good example of this. [https://www.sens.org/therapy-to-destroy-cells-with-reactivated-jumping-genes/] They sponsor both intramural [https://www.sens.org/our-research/intramural-research/]and extramural [https://www.sens.org/our-research/extramural-research/] research. Several longevity biotech companies such as Underdog Pharmaceuticals [https://underdogpharma.com/] has been spun out of research funded by SENS. The longevity biotech companies then take the technology through clinical trials. I encourage you to have a browse of the research they have funded, here. [https://www.sens.org/our-research/] LRI and SENS fulfil essentially the same role - to fund important research in this field, to increase the probability that effective anti-aging therapies will be discovered. I think LRI is also a good place to donate, though I am less familiar with their work.
2ChristianKl20dThere are two ways you can react to DeepMind making progress on protein folding. The one is to say: "Great there's progress". The other is to look at the inability of the existing companies to innovate. When Illumina started having their monopol on sequencing technology, the cost effectiveness of the technology suddenly stopped going down like is was before. After Theranos went bust we don't have new companies that go after cheaper blood tests even through that would be important to reduce the costs of understanding what happens. If we live in a world where we have a bunch of promising approaching for anti-aging drug development and our problem is that not enough capital goes towards persuing them, research that provides additional perspectives doesn't seem to be most important. If the model is that if SENS provides more approaches Greeves or Deming can fund more startups, the bottleneck isn't about moving exisiting approaches to trials.
2PeterMcCluskey13dBaze has technology for cheaper and more convenient blood tests. So far they're only using it to sell vitamins. I presume regulatory obstacles are delaying more valuable uses.
1JackH13dJust looked it up - looks promising. Thanks for sharing.
2JackH20dSorry, I don't quite follow - what's the point here? That funding SENS alone is unwise? If so, I don't think that's the major concern, as SENS has a tiny budget (~$5 million) and have a good track record funding some of the best work in the field. By 'approaches' I meant, 'therapeutic approaches', not 'perspectives on aging'. What I tried to emphasize in the OP is we have a good-enough model (or, 'perspective') on aging which is the hallmarks of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/], and that the limiting factor now is funding to (1) develop new approaches to therapeutically addressing these hallmarks and (2) translate these findings into humans through the financing of longevity biotech startups, though (1) is the more important than (2).
2ChristianKl17dI have two motivations here: (1) Having that argument between tool-spending and more application focused spending. Arguing that clash in detail is good for giving people an overview over it. The OpenPhil report on Mechanism for Aging [https://www.openphilanthropy.org/research/cause-reports/scientific-research/mechanisms-aging] asks here "How likely is it that general-application tools and basic research areas that might not be thought of as part of “aging research” (analogous to epigenetics, stem cells, neuroscience, and drug delivery) will be bottlenecks to accomplishing the core objectives described above? " (2) On average I think that tool research is not emphasied enough in biomedicine. It frequently happens that better tools make important new research possible. Thomas Kuhn argued that focusing to much on application usually leads to an academic field being very unproductive. When doing academic research you never know beforehand what you will find. Sometimes reserarch can evolve into a tool direction instead of an application direction. If a person is too much committed to an application direction (towards anti-aging) they might not persue valuable research directions. Similar things go when seeking jobs. I would expect that average person who works at DeepMind on protein folding to have a larger impact on ending aging then the average person at a biotech companies which has fighting aging as it's mission statement. In the large scale of funding, SENS budget is at the moment a rounding error, so I don't think that the extend towards which it's currently funded is a problem. I think it would be reasonable for SENS to have 10X the money it has but I'm doubtful 100X would currently be justified.
3JackH16dI gave a more thorough analysis of why OpenPhil [https://www.openphilanthropy.org/research/cause-reports/scientific-research/mechanisms-aging] missed the mark somewhat in their 'medium-depth' inquiry of anti-aging research in response to your comment lower in this thread, which is relevant to this point. I'll add a couple of points: I completely agree with you that technology from other areas (AI, platform technologies etc.) will benefit aging research. But that's not the point - 100,000 people per day are dying of aging and we have the tools to test a bunch of drugs, and a huge laundry list of possible drugs to test (AKG, Gemfibrozil, rapamycin, spermidine, etc.) but we don't have the funding to do it. So, donating to SENS is important to pick the lowest hanging fruit i.e. testing drugs we are already pretty sure do slow aging. To give an analogy - you could say that given advances in materials engineering would help us get to Mars, but you also need Elon Musk (or equivalent) to put the pieces together and do the thing. Anti-aging is the same - although today's platform technologies are not perfect (just like today's material science is not perfect) there are so many experiments we can perform now that would save potentially millions of lives, and should be prioritized. Remember that anti-aging almost certainly will happen eventually if society doesn't collapse, and what the field is fighting for is for this to happen sooner rather than later, so that many more people alive today will benefit. The above is actually an additional criticism I had of the OpenPhil. It's not that Aubrey de Grey and and others in the field don't think advances in other areas will help (AI, etc.), it's that there are so many feasible projects that should be funded that could potentially have a huge impact on populations today, that are not being funded. The neglectedness of the field is the primary reason SENS needs more funding, - think of SENS as funding a locus of research that has
2ChristianKl16dI think it's worth putting such a critique into it's own top-level post sooner or later. It more likely engage OpenPhil. And we have a very profit oriented industry that makes money with making good calls on judging which possible drugs as worth testing. It's relatively easy to make an argument that certain basic research that's valuable but not directly profitable are underfunded. The term valley of death is about drugs where we are not pretty sure that they have a clinically useful effect. There's no reason to believe that material science progresses in a way that makes building starship 10X cheaper within a decade unless people are working on the technology. On the hand there are plenty of experiments that are run in antiaging that plausibly could get 10X cheaper through tooling improvements.
2JackH15dWill do. If it works (slows aging) then it will be profitable. If by 'tooling improvements' you mean, biomarkers of aging then I completely agree with you. This is also research within the aging field that requires more funding. Besides that, I'm not sure what kind of tools you think we need. The bottom line is that we have a bunch of drugs, and we need a measuring stick (accurate biological age test) to tell us whether the drugs slow aging or not. What other platform technologies would be needed to expedite this process?

I'm in support of anti-aging research, and think we should fund it more highly, specifically because the long-term benefits are so high once we get it right. Does anyone have any comments on whether SENS is the best place to put money if you're interested in donating to anti-aging? 

As a side note, my experience working with complex codebases has led me to disbelieve your optimism for how quickly we can find reliable ways to get more than a decade of increased healthspan. The human body is vastly, vastly, vastly more complex than nearly any codebase hu... (read more)

5Victorel Petrovich12dYes, organisms (even worms) are way more complex than any codebase so far, and researchers don't fully understand them and yet - as you can see from this and other reviews - very significant lifespan (and healthspan) increases have been achieved. Even in mice and rats, which, aside from an inferior brain, are about as complex as humans. To me, this indicates that the aging process is quite malleable, with many ways to tweak it, which researchers are finding through theories, educated guesses and trial and error.
3JackH22d(1) Charity recommendations I would recommend donating to SENS Research Foundation [https://www.sens.org/get-involved/donate/] or Lifespan.io [https://www.lifespan.io/campaigns/join-us-become-a-lifespan-hero/]. SENS has funded a lot of really great research in the field, which you can view here [https://www.sens.org/srf-publications/]. Lifespan is involved in advocacy, and have been successful in hosting conferences and providing a platform for information sharing in the field. They have also crowdfunded some research [https://www.lifespan.io/how-it-works/]. Both the research and advocacy components are crucial for helping to expand the longevity field. (2) Complexity of aging Yes, the causes of aging are complicated - that is, how the damage accumulates - is complicated. But treating aging doesn't actually require understanding how the damage accrues, using the SENS (strategies for engineering negligible senescence) approach. It only requires how to ameliorate the various types of damage (hallmarks of aging). Bear in mind that overwhelming evidence in the past 20 years has suggested that all aging-related processes are, looking upstream, a result of the hallmarks of aging [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/] and that there is no other cellular phenomenon besides these 7-10 processes (depending on how they are classified) responsible for the aging process that cannot be reduced to them. In the past 20 years, no new hallmarks have been discovered and researchers are fairly confident that these are the only hallmarks there are to discover. Here's Aubrey de Grey's [https://www.fightaging.org/archives/2012/02/aubrey-de-grey-on-the-engineering-philosophy-of-sens/] explanation of the SENS approach: "The basic point we're making there is to contrast the regenerative approach with the more traditional idea of trying to make metabolism create molecular and cellular damage more slowly [https://www.fightaging.org/archives/2012/02/enthusiasm-for-th
2ChristianKl21dIs there any polling about how many of the anti-aging researchers believe this thesis?
4JackH21dTo the best of my knowledge, there has not been polling of this question to anti-aging researchers (geroscientists) specifically. However, if you watch lectures by anti-aging researchers [http://www.agingpharma.org/watch], and the major conferences such as ARDD, EARD, CSHL Mechanisms of Aging and so on, most of them seem to use this paradigm when discussing aging and many even have a slide on the hallmarks of aging. All of the big names such as David Sinclair, Brian Kennedy, Lynne Cox, Judith Campisi, Alex Zhavarankov, and many others all mention the hallmarks of aging. If you want further evidence, consider that the original paper, The Hallmarks of Aging (2013) [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836174/] published in the journal Cell is the most highly cited academic paper in the entire field - with over 6800+ citations. Although it was Aubrey de Grey who first conceived of the Hallmarks (which he called the '7 deadly SENS [https://www.sens.org/our-research/intro-to-sens-research/]' and categorised them slightly differently in his 2007 book, Ending Aging) it has now become the framework used by researchers in the field, and even included in academic courses - such as the lectures I was invited to give to clinical neuroscience students here at Oxford University about aging and neurodegeneration. So it's fair to say that it is now the consensus that the hallmarks of aging is the predominant view of the field, even though this was not the case 10-15 years ago when other theories of aging such as the free radical theory of aging [https://en.wikipedia.org/wiki/Free-radical_theory_of_aging]held more weight.
4ChristianKl21dIf you are in a position to be invited to such talks, it might be worthwhile to put information about your identity into your post. Maybe as part of a epistemic status tag on the top. The thing that's very unclear to me is why SENS has so little funding if that's framework is now consensus. It seems like while the metformin trial study seems like good value for money in contrast to typical NIH funding, funding it with a decade worth of SENS funds wouldn't be good value for money if SENS works. Why doesn't SENS succeed at having a 8 or 9 figure budget? Which arguments are keeping the billionaire money from funding it stronger while the metformin trial study did get it's money?
5Victorel Petrovich12dI guess one reason is that billionaires don't have time to do their research in detail, to see for themselves whether de Grey and Sens are worthy, but rely on reputation and opinions of popular names in the field. And the reputation of SENS seems to have suffered a bit initially, when many scientists found their proposals for rejuvenation too bold or futuristic https://en.wikipedia.org/wiki/Aubrey_de_Grey#Criticism [https://en.wikipedia.org/wiki/Aubrey_de_Grey#Criticism]
3JackH21dSENS Research Foundation aren't the only source of funding for research into the hallmarks of aging. The research into the hallmarks of aging labs at NUS, the Buck Institute, Oxford, Harvard and many other institutions is largely funded through the traditional route of national medical research councils. SENS Research Foundation funds some of the research, but by no means most of it. That said, they have a good track record of selecting some of the most important projects to fund despite a small budget of $5-10 million. For a point of comparison, the National Institute of Aging which as a $3 billion budget allocates around $100 million to geroscience.
1emanuele ascani17dBecause they choose the most neglected (long-term/difficult/high-risk high-reward) projects within the Hallmark framework (I talked extensively about this in my posts if you want to take a peek).
3ChristianKl17dWhy wouldn't billionaires (outside of Thiel and Greeves) that donate money for improving health outcomes want to fund long-term/difficult/high-risk high-reward projects? Do you know whether SENS request a grant from OpenPhil?
5JackH16dYes, and there are some signs that more billionaires (at least, the progressive-minded ones) are taking this seriously. For example, Elon Musk in an interview 3 weeks ago [https://www.youtube.com/watch?v=8HShn09BUh8] (timestamp: 24:03) mentioned the feasibility of 'stop[ping] aging' when asked about the biggest threats to the future of humanity, for the first time on the public record. Two scientific advisors from OpenPhil conducted a 'medium' depth investigation into anti-aging in 2017 [https://www.openphilanthropy.org/research/cause-reports/scientific-research/mechanisms-aging] and seemed to understand the problem, though were less optimistic about anti-aging timelines, and funding this research area. They made the following forecast: However, I would strongly disagree with this timeline, based on my knowledge of the field, today. I would go so far as to say that some combination of therapies available today - including metformin, senolytics, blood plasma exchange and epigenetic reprogramming - could already extend lifespan 25 years (compared to not taking the therapies) if personalised and multi-omics-biomarker [https://pubmed.ncbi.nlm.nih.gov/32084299/]-optimised. It's just that we need more research to know how, when, where and how much of these therapies are required for each individual. With another 46 years of research in a field that is already expanding, I have no doubt that 25-year lifespan extension will be available by 2067. They also summarised what a few of the anti-aging approaches (senolytics, stem cell therapies) but neglected many of the most promising approaches such as plasma exchange [https://www.lifespan.io/news/diluting-blood-plasma-rejuvenates-old-mice/], partial epigenetic reprogramming [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351826/], and mTOR inhibition [https://www.karger.com/Article/Fulltext/484629#:~:text=A%20growing%20list%20of%20evidence,in%20all%20model%20organisms%20studied.] . They also made a big mistake, in my opi
3ChristianKl16dYoutube allows you to link to specific timestamps [https://youtu.be/8HShn09BUh8?t=1443]when you click on the share button. I think there are two separate issues. One is about aging being taking seriously and the other is about SENS being taken seriously. I think you have the wrong link. In any case Aubrey de Grey basically here that hiring credentialed people is not enough to get results but that if he would organize the research it would produce better results. While that might be true it's hard to assess. That sounds like the people in the 1970s that they thought they could cure cancer by the end of the decade if they declare war on it.
1JackH15dThanks for the tip. Sorry, here [https://youtu.be/TquJyz7tGfk]is the link. It's not that hard to assess, given he has many informal chats with people affiliated with Calico. His point is that Calico has a huge budget but terrible internal structure that has essentially created an internal valley of death - many good aging researchers on good salaries, and many good pharma guys, but no-one who is actually developing and translating the technologies to solve aging (i.e. by repairing the hallmarks of aging). It's not an apt comparison for at two reasons: * Scientists were nowhere near understanding cancer in mice let alone curing it in 1970. By contrast, with anti-aging technologies such as senolytics we can already delay cancer (which kills 80% of mice typically) and extend healthy lifespan 30%. * Solving cancer is a potentially harder than slowing aging, since it involves intervening in the process further downstream i.e. when more damage has accumulated, rather than nipping it in the bud.
1emanuele ascani17dI dont't know actually (for both questions). And I'm not sure how many billionaires like this there are.

Is there any way for a small private investor to invest in this? By amount of risk, this is probably more of a charity than an investment, but with a small chance of hitting a jackpot.

Maybe some fund which invests into longevity projects? I could not find individual companies, which would be publicly traded.

1JackH7dHi icemtel, There are a number of publicly-traded longevity biotechnology companies. You could invest in Unity Biotechnology [https://unitybiotechnology.com/] (NASDAQ:UBX) or Proteostasis Therapeutics (NASDAQ:PTI), for example. I also recommend the Longevity Market Cap [https://sub.longevitymarketcap.com/] newsletter. For larger investments, you could also look into longevity biotech VC's such as Apollo Health Ventures. [https://www.apollo.vc/] Here are some links that may be useful: https://investoraccess.masterinvestor.co.uk/events/investing-in-the-age-of-longevity/ [https://investoraccess.masterinvestor.co.uk/events/investing-in-the-age-of-longevity/] https://transhumanplus.com/investments-on-antiaging/ [https://transhumanplus.com/investments-on-antiaging/] https://investingnews.com/daily/life-science-investing/longevity-investing/longevity-research-companies/ [https://investingnews.com/daily/life-science-investing/longevity-investing/longevity-research-companies/] https://www.nanalyze.com/2019/08/top-10-companies-longevity/ [https://www.nanalyze.com/2019/08/top-10-companies-longevity/]

On "Call to Action" : 
Besides sharing, learning and donation, why don't you encourage research-minded people to actually participate in / join the research? 

First, students or young researchers in position to choose or change their research direction.

Second, others: since the audience that will fully read such an article is likely to have useful research skills (biology, science, computer science etc ). Some may be willing to volunteer with their skills and join some project.

3JackH12dThanks for the tip - just added 'become a researcher' and 'work for a longevity biotech company' as additional ways to help the field.
1Victorel Petrovich3dThanks, the way you have included links to possible laboratories and companies is great!

Thank you for the great article!
One possible minor correction: turtles do senesce https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988574/

2JackH14dYou're welcome! I mentioned 'tortoises' rather than 'turtles' in the OP and was referring to species such as the Aldabra giant tortoise (Aldabrachelys gigantea). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743229/ [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743229/]
1Victorel Petrovich13dThanks for correcting me, I didn't know turtles and tortoises are different! Another example, at least as good, of negligibly senescent tortoise, is Gopherus agassizii https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157354/

I purely enjoyed the read about the State of the Art. I had no clue there's so much going on behind the scenes. 

If I may, I would like to steer the discussion from technology towards ethical and practical matters. 

The argument could go like this:

We're living on the cusp of technological progress. We (most western countries) enjoy easy access to more resources than we could ever consume and enjoy. The accessibility of the internet means we can communicate globally. We have cars and fridges and smart homes and Nicolas Cage pillowcases.  Y... (read more)

Your comment alludes to 3 exceedingly common objections to anti-aging: 
 
(1) 'Death and aging bring meaning to life' 

(2) Distributional justice (i.e. 'only for the rich') 

(3) Overpopulation (resource overconsumption, environmental impact etc.) 
 

All of these objections have been responded to at length by David Wood in his book The Abolition of Aging, Aubrey de Grey in his book, Ending Aging and David Sinclair in his book, Lifespan and on blogs such as FightAging.org and Lifespan.io

Anyway, I plan to write a Part 2 post covering the main ethical arguments including the three you reference, but will provide a short summary here: 

 

(1) 'Death or aging brings meaning (or happiness) to life'

My point is this: Age and suffering give meaning to our lives. Technology slowly but surely eliminates both. Without any struggle - and as close to paradise as ever - where will we find meaning? In continuous progress? In "higher" quality of life?* 

While chronological aging gives meaning to our lives, as existing over time allows to experience reality for longer (allowing for self-actualisation, building friendships and relationships, pursuing pass... (read more)

1Vanilla_cabs16dI am not under the impression that physical comfort is what was opposed in Fight Club. After all, hunter-gatherers also accessed more resources than they could ever consume, like top-quality fresh air and sunlight. I think it was consumerism. Under consumerism, consuming is not driven by personal motivation, but by the external general goal of supporting the economy. Instead of being an end, the consumer has to be turned into a means to that single end, a slave to consumption, through ads and social pressure.

Without aging, COVID-19 would not be a global pandemic, since the death rate in individuals below 30 years old is extremely low.

A pandemic is an epidemic that occurs across multiple continents. Note that we can accordingly envision a pandemic with a death rate of zero, but a pandemic none-the-less. Accordingly, I think you've somewhat overstated the punchline about aging and COVID-19, though I agree with the broader point that if aging were effectively halted at 30, the death rates would be much, much lower.

4JackH17dThat's a reasonable challenge. However, the definition you cited (from Wikipedia) is the classical definition of a pandemic [https://www.who.int/bulletin/volumes/89/7/11-088815/en/], and according to the WHO, does not take into account disease severity and transmissability, and would imply relatively harmless influenza outbreaks would also classified as pandemics [https://www.who.int/bulletin/volumes/89/7/11-086173/en/] - which is somewhat controversial in terms of definition. So depending on how you define a 'pandemic' (i.e. with or without disease severity and transmissibility taken into consideration) my original claim may be true.
1AABoyles16dFair point. It does seems like "pandemic" is a more useful category if it doesn't include a whole bunch of "things that happened but didn't kill a lot of people."

"Recently, a group of Russian biohackers recently performed..."

Just reporting a little mistake here.

Good overview.

1JackH19dThank-you, fixed.

Regarding parabiosis, are you familiar with the Conboy's research on diluted blood plasma? I know they are trying to get a trial going -- but suspect the effort has been a bit delayed due on the main event for 2020.

2JackH20d

A very long article about anti-aging and not a single mention of the effect of insulin and carbohydrates on ageing. No mention of the use of a ketogenic diet as an anti-ageing strategy. 


At least you mentioned Metformin... 

8JackH7dHi bardstale, 'Deregulated nutrient sensing' is one of the 9 hallmarks of aging covered in the article, and includes insulin signaling (IGF-1, etc) [https://www.lifespan.io/news/hallmarks-of-aging-deregulated-nutrient-sensing/] - that is, insulin signaling pathways. Dietary protocols such as the fasting-mimicking diet (FMD) [https://stm.sciencemag.org/content/9/377/eaai8700?utm_source=6&utm_medium=social&utm_campaign=Science-Translational-Medicine-%28ScienceTranslationalMedicine%29&utm_term=SciMag&utm_content=AAAS&fbclid=IwAR21ygQWQJPrff4joF39o_8pabP-mwxhj8rovQQ45UTpJQ4BfRvNX_fP5oI] and ketogenic diets [https://pubmed.ncbi.nlm.nih.gov/10812493/] attenuate IGF-1 which is potentially beneficial for longevity. However, lifestyle protocols were not the focus of this article, since ultimately, lifestyle interventions alone are not likely sufficient to extend maximal lifespan beyond 125 years. Another way to phrase this, is that these diets are 'anti-aging' insofar as they slow the rate of aging, but not reverse it to a level that could potentially be achieved with therapies. The goal of anti-aging research is to provide new therapies that can allow us to live much longer than is available with the best approaches today (diet/exercise/meditation/low stress etc.).
2icemtel8dWhy don't you provide some references for other readers?

It seems to me that unlike say, GAI research very little attention has been paid to the consequences of such work. I do not see how this would not result in a tiered society where at least at first those with access to longevity will be the wealthy and resourceful and thus able to tyrannise those that dont.

There are then of course a myriad of psychological/existential implications which someone like Scott Alexander would have a field day with. How can we give our time meaning if we have an unlimited amount of it? What about personal relationships? Or voca... (read more)

2JackH16dThis is true, and indeed there has been very little social sciences research on longevity that I am aware of, besides public attitudes towards longevity [https://www.tandfonline.com/doi/abs/10.1080/15265160903318368]. Given the highly probable rise of anti-aging technologies in the near future, social science should focus its attention on modeling the impacts of longevity on social systems, political systems, and so on. Distributional justice is a very common objection to life extension that has been addressed at length by many in the field. This article [https://www.lifespan.io/news/only-the-rich/] and this site [https://agingbiotech.info/objections] do a good job at laying out the arguments, and David Wood [https://www.youtube.com/watch?v=_6Wz6XxUb0E&t=665s] who I recently interviewed discusses this point, as he does in great depth in his book, The Abolition of Aging. I'll summarise some of the responses to distributional justice (i.e. 'only for the rich') arguments below: * Anti-aging therapies are in principle no different from existing medical treatments such as anti-viral or anti-cancer therapies. For example, there is little philosophically difference between a cancer therapy (e.g. molecules that kill cancer cells) to extend healthy lifespan and a senolytic drug (e.g. molecules that kill senescent cells) to extend healthy lifespan. In the same way that few would object to the development of better cancer therapies today (e.g. CAR T-cell therapies) that only the rich can afford (and are not, for example, currently available to people in Africa), few should object to anti-aging drugs that extend healthy lifespan, even if only the rich can initially afford them too. Basically, many lifesaving medical interventions are initially expensive, and therefore only available to the rich, but this isn't a reason to inhibit research. An additional point: if you support current medical research - which functions essentially to exten