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Anti-Aging: State of the Art

by JackH10 min read31st Dec 202027 comments

67

AgingLife ExtensionWorld Optimization
Frontpage
Anti-Aging: State of the ArtPart I: Why is Aging a problem?Part II:
What does a world without aging look like?Part III: What is aging?
Where does this 'damage' come from?Anti-aging vs current medicinePart
IV: Can aging actually be slowed?Part V: Most promising anti-aging
strategies1. Parabiosis (blood exchange)2. Metabolic manipulation
(mTOR inhibitors)3. Senolytics - drugs that kill senescent cells4.
Cellular reprogramming5. Additional anti-aging approachesPart VI:
ConclusionPart VII: Call to ActionPart VIII: Learn moreBooks:YouTube:
Websites and blogs:Good review articles:
27 comments

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 day 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):  

[M2TQ7O0pAT]Source: here

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&
apos; - 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 does 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): 

[O2yg9wX-r9]

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:

[HHdD7WZSwX]

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. 

 

[l53p2_tmCv]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):

[C9LS0EQycp]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. 

[q38sn6gxwE]

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%: 

[Fvu1uifTvc]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:

[uPmetMG6cL]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:  

[wPLEZgABpl]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 performed 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.

[Mmleu3N_lA]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. 

[yi9y3o-vWm]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):  

[79OnNbLI9n]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): 

[ctIa3PIgqF]

 

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. 

 

[8NKzzC89k9]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. 

[oIMJ6Pcoza](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. 

[Xwcgn06QSu]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:

  * Sharing this post with others
  * Joining the Longevity subreddit or the Lifespan Discord server to
    plug in to longevity channels
  * Learning more about the field by reading the suggested materials
    below
  * Donating to the SENS research foundation. They fund the most
    neglected and high-impact research in this field as explained in
    this LessWrong post.

 

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

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[-]Natalia Mendonca17h 8


    [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.

Reply
[-]JackH12h 6

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:

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.
     

Pharmacological:

On the safer end (for younger people or people with a lower risk
tolerance):

  * Metformin - calorie restriction mimetic that controls blood sugar
  * Quercetin - anti-aging flavenoid that acts as a senolytic
  * Resveratrol - sirtuin enzyme activator and calorie restriction
    mimetic
  * Vitamin D - blood tested to optimize, ideally 2000IU per day
  * Vitamin B12 - as many people are deficient

On the more extreme end (for older people or people with a higher
risk tolerance):

  * Rapamycin - an mTOR inhibitor that attenuates senescence
  * NAD-boosters such as NMN and NR - enhancers of stem cell function
  * Dasatinib - a senolytic usually used in combination with
    quercetin

In my cupboard at home, I have a bunch of these pills, as do other
people involved in this field who are involved in this research. If
you watch interviews from Harvard aging researcher David Sinclair,
you will see he takes these supplements, as do many of his millions
of followers. These are probably a good starting point given Sinclair
is one of the most knowledgeable and researchers in the field.

Ultimately, much or all of the above strategies will be superseded by
superior anti-aging technologies in the future (gene therapies,
nanotechnologies etc.) but they are a good starting point for
increasing longevity and bringing more awareness to the field. 

A nice article about a 32-year old biohacker who spent $200k on
biohacking his health based on the research is here. 

Regarding (2), there are many ways to contribute to the field:

  * Become a Lifespan.io hero (subscriber)
  * Donate to SENS Research Foundation
  * Learn more about the field and discuss it with others, to
    increase public awareness of the field to help increase:
      + Government expenditure in geroscience research, which is a
        crucial bottleneck
      + Larger private donations to organizations like SENS
      + Financing of longevity biotech startups
         

The above are important actions since funding into the basic
geroscience research is a key rate-limiting step in progressing the
field. There is a fair amount of money to finance the longevity
biotech companies, but funding for geroscience is pitifully small -
less than 0.2% ($100 million) of the NIH's $45 billion budget, even
though the NIA for example, has a budget of around $3 billion.
Moreover, organisations such as SENS finance some of the best
research in the field have even smaller budgets ($5-10 million) which
is why private small donations can still have a significant impact. 

Reply
[-]Matthew Barnett16h 7

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 practical
purposes, cured cancer in mice, but the results have not yet
translated into humans. Whether or not this claim is true, it's clear
that progress has been slower than the starry-eyed optimists had
expected back in 1971.

That's not to say that there hasn't been progress in cancer research,
or biological research more broadly. It's just that progress tends to
happen gradually. I don't doubt that we can achieve modest success; I
think it's plausible (>30% credence) that we will have FDA approved
anti-aging treatments by 2030. But I'm very skeptical that these
modest results will trigger an anti-aging revolution that
substantially affects lifespan and quality of life in the way that
you have described.

Most generally, scientific fields tend to have diminishing marginal
returns, since all the low-hanging fruit tends to get plucked early
on. In the field of anti-aging, even the lowest hanging fruit (ie.
the treatments you described) don't seem very promising. At best,
they might deliver an impact roughly equivalent to adding a decade or
two of healthy life. At that level, human life would be meaningfully
affected, but the millennia-old cycle of birth-to-death would remain
almost unchanged.

    Today, there are over 130 longevity biotechnology companies

From the perspective of altruistic neglectedness, this fact counts
against anti-aging as a promising field to go into. 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. One more researcher, or one more
research grant will add little to the rate of progress.

In my opinion, if robust anti-aging technologies do exist in say, 50
years, the most likely reason would be that overall technological
progress sped up dramatically (for example, due to transformative AI
), and progress in anti-aging was merely a side effect of this wave
of progress. 

It's also possible that anti-aging science is a different kind of
science than most fields, and we have reason to expect a
discontinuity in progress some time soon (for one potential argument,
see the last several paragraphs of my post here). The problem is that
this argument is vunerable to the standard reply usually given
against arguments for technological discontinuities: they're rare. 

(However I do recommend reading some material investigating the
frequency of technological discontinuities here. Maybe you can find
some similarities with past technological discontinuities? :) )

Reply
[-]JackH11h 5

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 these therapies may not
translate to humans. However:

Human trials for aging specifically for three of the four approaches
I mentioned are currently underway, but the lack of human data for
these approaches ought not to undermine the scientific feasibility
of, given results of other trials in humans. Data from human trials
suggest many of these approaches have already been shown to reduce
the rate of cognitive impairment, cancer, and many other features of
aging in humans. Given these changes are highly correlated with
biological aging, the evidence strongly suggests the capacity for the
approaches mentioned to slow biological in humans. 

In addition, in the past 2 years, human biological aging has already
been reversed using calorie restriction, and with thymic rejuvenation
, as measured by epigenetic (DNAm) aging. DNAm aging is fairly
accurate in predicting time-to-death due to age-related conditions,
so this is a promising finding for the field. Once more clinical
trial data comes in, it will be easier to evaluate, but the
preliminary evidence has demonstrated biological aging can be slowed
in humans in the near future. 

Regarding tractability, it's also worth noting that the above has
been made despite the research field receiving such comparatively
little funding (explained in (2)). 

Of course, part of the research in anti-aging is to develop more
accurate biomarkers of aging (e.g. multi-omics biomarkers of aging),
since it's inherently a difficult process to measure. Funding in the
field is required to develop better biomarkers of aging so that we
can indeed provide more robust evidence that aging can be slowed in
humans. Neverless the limited tools we have to measure aging (e.g.
DNAm/Horvath's clock, Levine's clock) there has been sufficient
proof-of-principle that aging in humans can be slowed to suggest that
time-scales for anti-aging are fairly short, or could be with
increased funding. 


(2) Neglectedness

I understand that the number of longevity biotech companies may
(wrongly) suggest that the field is well-funded. But this number is
not an accurate proxy for the relative funding received by basic
geroscience to develop cures for aging, from which these companies
are spun-out of. 

The crucial point is that although there is a lot of money in 'aging'
in general (e.g. NIA's budget of $3 billion), and a lot of private
money to finance longevity biotech companies spun out of basic aging
research laboratories, there is a pitifully small amount of money
financing basic geroscience research to find therapies to treat
aging. This is especially true when compared to any other biomedical
field, such as cancer, or neurodegeneration, which receive 1-2 orders
of magnitude greater funding (e.g. NCI has an annual budget of $6.5
billion, compared to $100 million for geroscience research). I think
many EA's assume academia is an efficient market that will
self-correct to prioritise research with the greatest potential
impact; but unfortunately, that's not how things work due to the
incentives in academia. For example, cancer researchers have no
incentive to start investigating aging, since it's outside the scope
of their grant funding. Until the public realizes aging is a problem,
and lobby governments to increase expenditure towards geroscience,
the rate of progress remains comparatively slow, given what it could
be. 

To give some numbers: Less than 0.2% ($100 million) of the NIH's $45
billion budget goes towards geroscience research to find cures for
aging, even though the NIA  has a budget of around $3 billion.
Moreover, organisations such as SENS finance some of the best
research in the field have even smaller budgets ($5-10 million) which
is why private small donations can still have a significant impact. 

Aubrey de Grey who has significant insight into the landscape of
funding for anti-aging believes that $250-500 million over 10 years 
is required to kickstart the field sufficiently so that larger
sources of funding will flow in. In most timelines, this will happen
inevitably, but given 100,000 lives are lost per day until we reach
longevity escape velocity, getting to these milestones as soon as
possible is a key priority, and the numbers suggest doing so
represents one of the most cost-effective cause areas. 

Other comments: 

(1) Timelines
Regarding timelines and predictions, I think regardless of whether
the FDA approves senolytics by 2030 or not, which is primarily a
question of bureaucracy and politics more than science, the more
interesting question is do senolytics actually work to slow aging. I
would put the probability at 90% that one or more type of senolytic
or senotherapeutic compound extend healthy lifespan by 5 years or
more on average in humans if taken from a young enough age,
regardless of whether they sufficiently meet the endpoints for
specific disease indications required for FDA approval. 

(2) AI
I agree that AI, if it doesn't kill us all will probably have a huge
impact on solving aging. However, this doesn't actually change my
calculus as the importance of solving aging very much, given that
most AI timelines imply millions or billions of people will most
likely die of aging before aging is solved by AI, unless we have
anti-aging drugs to keep as many people alive as possible in the
meantime. 

Developing anti-aging compounds 'by hand' without the help of AI may
seem slow and inefficient, but remember that we don't need to achieve
negligible senescence before AI - we only need drugs that are
sufficiently effective to bring as many people as possible to the
point in time at which AI solves aging. For example, a drug or
cocktail of therapies that extend life of all humans on Earth by 10
years essentially allows 10-years' worth of people who would
otherwise have died of aging (~400 million people) to potentially
reach the point at which AI solves aging and hence, longevity escape
velocity. From an EA perspective, this seems like an incredible
amount of good, and far better than most other cause areas out there,
barring x-risks like AI safety. 

(3) Starry-eyed optimism
Current evidecne suggests curing in cancer is probably much harder
than slowing aging, because you have to reverse the damage associated
with aging (which predisposes to tumorogenesis) as well as kill of
the cancer to restore a person to a state of health, since aging
alters the tumor microenvironment in a way that causes cancer.
Therefore I'm not sure how apt the analogy is. 

An analogy that is often thrown around in anti-aging circles is that
of flight, which had a remarkably short timeline, or the Apollo
missions. David Wood in his book, The Abolition of Aging makes a good
case for how anti-aging could follow a similar timeline to flight. 




 

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[-]Matthew Barnett17m 2

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 might be competitive with
longtermist charities here.

    Data from human trials suggest many of these approaches have
    already been shown to reduce the rate of cognitive impairment,
    cancer, and many other features of aging in humans. Given these
    changes are highly correlated with biological aging, the evidence
    strongly suggests the capacity for the approaches mentioned to
    slow biological in humans.

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,

    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.

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. 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. Humans aren't
going to just suddenly realize that their whole ethical system is
flawed; that rarely ever happens.

More likely, we will see gradual progress over several decades. I'm
unsure whether the overall project (ie. longevity escape velocity)
will succeed within my own lifetime, but I'm very skeptical that it
will happen within eg. 20 years.

    In addition, in the past 2 years, human biological aging has
    already been reversed using calorie restriction, and with thymic
    rejuvenation, as measured by epigenetic (DNAm) aging.

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.

The recent progress in epigenetic clocks is promising, and I do think
that's been one of the biggest developments in the field. But it's
important to see the bigger picture. When I open up old Alcor
Magazine archives, or old longevity books from the 1980s and 1990s, I
find pretty much same arguments that I hear today for why a longevity
revolution is near. People tend to focus on a few small laboratory
successes without considering whether the rate of laboratory
successes have gone up, or whether it's common to quickly go from
laboratory success to clinical success. 

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.

    I understand that the number of longevity biotech companies may
    (wrongly) suggest that the field is well-funded. But this number
    is not an accurate proxy for the relative funding received by
    basic geroscience to develop cures for aging, from which these
    companies are spun-out of. 

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?

    I think many EA's assume academia is an efficient market that
    will self-correct to prioritise research with the greatest
    potential impact

Interestingly, I get the opposite impression. But maybe we talk to
different EAs.

    Aubrey de Grey who has significant insight into the landscape of
    funding for anti-aging believes that $250-500 million over 10
    years is required to kickstart the field sufficiently so that
    larger sources of funding will flow in.

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.

    For example, a drug or cocktail of therapies that extend life of
    all humans on Earth by 10 years essentially allows 10-years'
    worth of people who would otherwise have died of aging (~400
    million people) to potentially reach the point at which AI solves
    aging and hence, longevity escape velocity.

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.

Reply
[-]Chris Hibbert5h 1


    I once heard from a cancer researcher that we had, for all
    practical purposes, cured aging in mice, but the results have not
    yet translated into humans.

 

This 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. 

Reply
[-]Matthew Barnett4h 2


    This seems untrue on its face. What we mean by "curing aging" is
    negligible senescence.

And 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?

Reply
[-]JackH3h 2

I 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). 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, and LEV occurring by 2036.

Reply
[-]Matthew Barnett1h 2

Oops, that was a typo. I meant curing cancer. And I overlooked the
typo twice! Oops.

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[-]AllAmericanBreakfast1d 3

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.

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[-]JackH10h 5

(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.io.

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[-]AllAmericanBreakfast5h 2

Thanks 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.

Reply
[-]T3t1d 3

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!

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[-]ChristianKl7h 2

It 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/ 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? 

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[-]avturchin6h 2

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 oa 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?

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[-]JackH5h 4

Yes, we need improved biomarkers of aging. 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 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. 

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. 

Reply
[-]pjeby5h 2


    already known to be safe interventions, like vitamin D

Any 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.

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[-]avturchin2h 2

It is safe enough to be sold OTC, and there are some research 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.

Reply
[-]JackH4h 2

For a good summary video on vitamin D and aging, I recommend this.
For academic papers and other articles, I recommend this, this and
this. 

For information on personal longevity strategies, I recommend the
following:

- Watching videos by Dr Rhonda Patrick, Dr Peter Attia and Dave
Asprey
- Joining Facebook biohacking groups such as this, and this. 
- Joining the Lifespan discord server and reading comments on the
'personal longevity strategies' channel.

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[-]Yoav Ravid5h 1

Another option is to advocate for emergency authorization for old
people.

Reply
[-]avturchin2h 2

Unfortunately, it seems that most intervention works before aging
actually developed, so we need to give them to younger people, at
least before 50.

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[-]JackH2h 1

This is not true. Aging doesn't develop, rather, it is an ongoing
process of damage accumulation (i.e. hallmarks of aging) 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.

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. 

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[-]avturchin16m 2

That 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!

Reply
[-]Gerald Monroe21h 2

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 you also
attach a simulated or robotic human body (a body with sufficient
fidelity), and train the robot or simualated body with an appropriate
environment, the 'being' inside the box will eventually achieve
sentience and develop skills humans are capable of developing.

But you don't have to choose the weights at random.  If you obtain
just 1 bit of information from a frozen brain sample, you can use
that bit to bias your random rolls, reducing the possibility space
from "any brain possible within the laws of nature" to "a subset of
that space".

If you have an entire frozen brain, with whatever damage cryonics has
done to it, and you first slice and scan it with electronic
microscopes, you still get a lot more bits than just 1.  You will be
able to instantiate a brain that has at least some of the
characteristics of the original.  Will they have clear and coherent
memories (as coherent as humans have...)?  Depends on the quality of
the sample, obviously.  

But regardless of damage you can bring each cryonics patient 'back',
limited by the remaining information.  This is actually no different
than caring for a patient with a neurodegenerative disease, except
that the brain box will not have any flaws in it's circuitry and once
instantiated, the being occupying it will be able to redevelop any
skills and abilities they are missing.

Now, yes, trying to 'repair' a once living brain to live again as a
meat-system is probably unrealistic without technology we cannot
really describe the boundaries of.  (as in, we can posit that the
laws of physics do let you do this if you could make nanoscale waldos
and put all the pieces back together again, but we can't really say
with any confidence how feasible this is)

Reply
[-]JackH11h 2

Hi Gerald, 

In the original article, I linked to Alcor's calculation of the
probability that cryonics works. It ranges from 0.2-77% 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. 

Reply
[-]shminux1d 2

Do we understand why cats live longer than dogs?

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[-]freyley29m 1

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
humans have developed, and less well factored by far. And working to
make notable improvements to complex codebases that are well-factored
still takes years of dedicated effort, with much better tooling than
we have for modifying the body. 

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