Anti-Aging: State of the Art
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.
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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 ...
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...
I appreciate the detailed and thoughtful reply. :)
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.
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,
Longevity research occupies an unstable position in the space of possible EA cause areas: it is very "hardcore" and "weird" on some dimensions, but not at all on others. The EAs in principle most receptive to the case for longevity research tend also to be those most willing to question the "common-sense" views that only humans, and present humans, matter morally. But, as you note, one needs to exclude animals and take a person-affecting view to derive the "obvious corollary that curing aging is our number one priority". As a consequence, such potential supporters of longevity research end up deprioritizing this cause area relative to less human-centric or more long-termist alternatives.
I wrote a post about how anti-aging mi...
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
I agree with Pablo's reasoning as to why anti-aging has not taken off in the EA community.
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.
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 was great.
Some things that made it great:
- 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).
- It was written clearly.
- 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.
Thanks 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.
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...
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:
- Is Human Life Extension Possible? - LongevityAdvice.com
- Longevity FAQ - Laura Deming (who is a longevity biotech VC)
- Lifespan by David Sinclair
- Ending Aging by Aubrey de Grey
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 ...
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...
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, ...
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?
[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 be...
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:
- Exercise - attenuates many hallmarks of aging
- Intermittent fasting - improves metabolic switching and cellular stress resistance
- Maintain strong social ties - social relationships are a strong predictor of lifespan
- Overcome depression, which accelerates biological aging
- Optimize your circadian rhythm
- Take a biological age test such as myDNAage or InsideTracker and monitor your age over time.
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 ...
I read this post at the same time as reading Ascani 2019 and Ricón 2021 in an attempt to get clear about anti-aging research. Comparing these three texts against each other, I would classify Ascani 2019 as trying to figure out whether focusing on anti-aging research is a good idea, Ricón 2021 trying to give a gearsy overview of the field (objective unlocked: get Nintil posts cross-posted to LessWrong), and this text as showing what has already been accomplished.
In that regard it succeeds perfectly well: The structure of Part V is so clean I suspect that it...
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!
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...
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.
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:
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:
...
- (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.
- (from the “damage” school) The body accumulates damage as we get older. The body tries to rescue itself from the damage by upregulating repai
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?
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!
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?
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"
I may argue against the anti aging field (and probably now that i reflect about it, it seems more important than most non-essential productivity in society) that it is highly more probable that we reach an agi singularity during our lifetimes, before we die of aging. (depends on your age).
What do you think?
I don't have the skills nor the time to review this post properly, but I think it's very good and it helped me understand the state of the art of anti-aging, so I think it should be part of the review.
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.
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.
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...
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...
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
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?
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...
Hi! The link under the "Processes of Cellular reprogramming to pluripotency and rejuvenation" diagram is broken.
I apologize for tldr. I think the most important thing is to prevent death of cells from low oxygen. If you solve he problem of nervous tissue dying from lack of oxygen, then you solve all coom problems like drowning, heart attacks, etc. Anything that cuts off oxygen will not kill you and. You will be invincible like a cockroach.
For me, the case for doing this has not sufficiently been made. I read two sets of arguments for it. On this page, essentially, "aging is the leading cause of death," which is funny -- like engagement is the leading cause of marriage -- but more seriously: to attempt to abolish aging is largely about fighting death. Pointing out aging kills doesn't take us anywhere until we've shown death needs to go.
On the linked page about "pro-aging trance," it was that if I'm still asking that question, I must be in a trance, and that's not exactly sound.
I don't have c...
Partial reprogramming in mice has shown promising results in alleviating age-related symptoms without increasing the risk of cancer.
Actually, it's not really known whether or not partial reprogramming increases the risk of cancer.
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.
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.
Thank you for the great article!
One possible minor correction: turtles do senesce https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988574/
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.
"Recently, a group of Russian biohackers recently performed..."
Just reporting a little mistake here.
Good overview.
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.
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?
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...
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...
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:
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:
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.
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):
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%:
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:
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:
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.
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.
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):
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.
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.
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.
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.