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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 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.
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. Humans aren't going to just suddenly realize that their whole ethical system is flawed; that rarely ever happens.
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. 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 and they began making use of these vaccines.
So, the goal isn't necessarily to persuade the world to consider aging a problem. It's to convince enough people with the capacity to speed up the research to become interested, so that the first generations of anti-aging therapies come into the world, and have strong evidence behind them, after which people will begin taking them.
Tractability:
I don't think either of these results are strong evidence of recent progress. Calorie restriction has been known about for at least 85 years. The thymic rejuvenation result was a tiny trial with ten participants, and the basic results have been known since at least 1992.
Regarding calorie restriction, the key significance of this finding was that this is one of the first indications that a marker of biological aging (DNA methylation age) has been significantly modulated using an intervention. This is a big step up from lifespan studies using calorie restriction in mice, since as you noted, not all interventions in mice translate well to humans.
Given that 86 percent of clinical trails eventually fail, and the marginal returns to new drug R&D has gone down exponentially over time, I want to know what specifically should make us optimistic about anti-aging, that's different from previous failed predictions.
This is a reasonable concern to have, and one that many outside of the field (i.e. not attending the conferences, not having kept up to date with the literature) do have. I too shared this view when I was studying neuroscience, before I started becoming more involved in the field.
What makes it different is that anti-aging is targeting the root cause of the problem, rather than the symptoms of the problem. So although 86% of clinical trials fail, this is because the approach to most of these trials (sick-care, essentially) that attempt to treat chronic diseases such as cancer, heart disease, awithout treating the root cause (aging) is ineffectual. Let's take Alzheimer's disease for example. This is a neurodegenerative illness that emerges as a result of decades of damage accumulation associated with the hallmarks of aging. Now, attempting to cure Alzheimer's without treating any of the underlying damage that continues to perpetuate the disease (such as senescent cells, mitochondrial dysfunction and other hallmarks of aging) is clearly ineffectual. How are you going to reverse the huge amount of molecular damage that occurs in the brain due to Alzheimer's, if you are not addressing the root causes of this damage, such as senescent cells, which are continuing to secrete pro-inflammatory factors that are driving neurodegeneration? Hence, it's really no surprise that over 100 clinical trials for Alzheimer's have failed and the $5.6 billion spent on trying to treat Alzheimer's since the approach is misguided. It's a similar story for cancer, too. There is a multi-decade long process of damage accumulation that alters the microenvironment that predisposes to tumorogenesis. So again, simply attempting to kill the tumor without attenuating the underlying damage that predisposes to tumorogenesis is clearly an ineffective approach. By contrast, anti-aging is targeting the common causes of all of these age-related diseases (senescent cells, etc.), and the preliminary evidence in mice and humans suggest that this is not just theory - it works in practice to extend healthy lifespan.
A few other comments about tractability:
There is a huge range of therapeutic approaches that have a reasonable chance of slowing or reversing aging in the future besides those mentioned in the article, including nanotechnology (companies like Alzeca Biosciences and Bikanta), gene therapy to treat the cause of multiple diseases at once, 3D-printed organs, and research is now being augmented by AI platforms for anti-aging drug discovery. Importantly, the same could not be said as recently as 5 years ago, when these approaches had not been developed.
If you are still skeptical, considering watching this summary of the state of the field in 2020 by Bill Falloon from RAADfest 2020 and all of these lectures from ARDD 2020 and see if you still think that meaningfully slowing aging is not likely in the near future.
If the number of companies working on rejuvenation biotechnology did not accurately represent the amount of total effort in the field, then what was the point of bringing it up in the introduction?
To demonstrate to readers that anti-aging is a real thing, and a legitimate field of biomedical research that they can support, rather than a whimsical sci-fi fantasy. That said, the field needs more support.
I don't doubt Aubrey de Grey's expertise or his intentions. But I've heard him say this line too, and I've never heard him give any strong arguments for it. Why isn't the number $10 billion or $1 trillion? If you think about comparably large technological projects in the past, $500 million is a paltry sum; yet, I don't see a good reason to believe that this field is different than all the others. Moreover, there is a well-known bias that people within a field are more optimistic about their work than people outside of it.
He is forecasting, so there's going to be some uncertainty. I don't know what evidence he could really draw on, since this figure is based on his impression on the current state of the entire field. But it's probably something like, his estimation of the marginal increase in progress towards achieving negligible senescence associated with increased funding, based on the marginal increase in progress associated with SENS' existing funding. The progress the SENS-funded projects have made is significant, and if you extrapolate that out to the best of one's abilities, you probably get something like the $250-500 million figure. Remember that this is not the total amount needed to make meaningful progress on aging, which indeed is probably in the order of many billions or tens of billions. But, the field fortunately is well placed to take advantage of huge leverage opportunities, since big pharma are watching closely to see how the field develops (I can dig up some reviews about this) as are other stakeholders. Once sufficient de-risking has been done, which is what that initial $250-500 million is needed for, bigger players are likely to enter the game and the field will take off. The public will also start taking note, since the $250-500 million is very likely to be enough to fund research that yields legitimate first-generation anti-aging therapies, enough to pique the public's interest. Ultimately, given the biggest bottleneck is funding, and every few million to make a new discovery or promising geroprotective compound results in tens of millions flowing in to finance the longevity biotech company spin-outs of these findings, that $250-500 million for SENS really looks more like $10 billion+ for the field as a whole. To clarify though, this is probably hard for those outside the field who are not familiar with longevity biotech financing to conceptualize, and I plan to write a separate post about this explaining it in more detail.
This is only true so long as the drug can be distributed widely almost instantaneously. By comparison, it usually takes vaccines several decades to be widely distributed. I also find it very unlikely that any currently researched treatment will add 10 years of healthy life discontinuously. Again, progress tends to happen gradually.
If you don't think that some combination of multi-omics-aging-biomarker-optimised combination of senolytics, mTOR inhibitors, gene therapies, nanotech, parabiosis, epigenetic reprogramming, exercise protocols, diet, 3D-printed organs - all of which are technologies available today - could extend life by 10 years, I'd be curious to know why. Even David Sinclair in his book Lifespan and interview explains that metformin+exercise+not smoking+intermittent fasting alone adds 14 years of healthy life.
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.