Anti-Aging: State of the Art

by JackH16 min read31st Dec 2020162 comments

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

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

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

 

Part I: Why is Aging a problem?

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

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

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

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

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

 

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

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

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

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

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

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

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

 

Part III: What is aging?

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

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

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

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

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

 

Where does this ‘damage’ come from?

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

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

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

 

Anti-aging vs current medicine

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

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

 

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

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

 

Part IV: Can aging actually be slowed?

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