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Humans have been obsessed with eternal youth for thousands of years. The search for elixirs, tonics, and the philosopher’s stone can be traced back to ancient civilizations. Only in the 1990s, however, did research show that lifespan may be modifiable. Pathways such as mTOR and insulin/IGF-1 were identified, and the field gained respect in academia. More recently, longevity research has exploded. The seminal paper, “The hallmarks of aging,” established nine common denominators of aging that appear during the aging process, accelerate aging if accentuated, and slow the aging process if improved.
It was updated to twelve hallmarks in 2023, which are listed below:
- genomic instability (DNA damage and mutations)
- telomere attrition (shortening of the protective caps at the end of chromosomes)
- epigenetic alterations (reversible DNA modifications that turn genes on and off, such as DNA methylation or histone modification)
- loss of proteostasis (accumulation of misfolded or damaged proteins)
- disabled macroautophagy (inability to remove damaged proteins, organelles, or cells)
- deregulated nutrient sensing (poor detection of energy and nutrient availability)
- mitochondrial dysfunction (inefficient energy production)
- cellular senescence (“zombie cells” that can’t divide anymore but secrete inflammatory signals)
- stem cell exhaustion (loss of ability to repair and regenerate tissue)
- altered intercellular communication (cells no longer communicate effectively, leading to inefficiencies)
- chronic inflammation (constant, low-grade immune response)
- dysbiosis (imbalance of microbes)
This blog post will focus primarily on stem cell exhaustion.
What is stem cell exhaustion and how does it accelerate aging?
As you age, your body’s repair cells, known as stem cells, slowly lose their ability to regenerate tissue. Before they are “exhausted,” stem cells replace worn-down cells, repair damage, and respond to injury. They can make more of themselves (self-renewal) and turn into different types of specialized cells (differentiation). However, over time, they decrease in number, divide less effectively, lose functionality, and even accumulate DNA damage. They become less efficient at repairing your tissues. This is why you experience thinning hair, slower wound healing, muscle loss, and a weaker immune system as you age. Your stem cells have become exhausted. Other hallmarks of aging contribute to stem cell exhaustion, which in turn accentuates other hallmarks of aging, creating a perpetuating cycle of decline.
Examples of stem cell exhaustion and their effects
- Hematopoietic (blood) stem cells (HSCs)
The decline in HSCs weakens the immune system, increasing infection risk and reducing vaccine effectiveness.
- Satellite cells (muscle)
With decreased repair of muscle, there is reduced strength and slower recovery.
- Skin cells
Skin can take longer to heal from cuts and bruises, as well as lose elasticity and wrinkle.
- Intestinal stem cells (gut)
If the gut cannot regenerate, nutrients are absorbed less efficiently, and the permeability of the intestinal lining is increased. This leads to inflammation and dysbiosis – two other hallmarks of aging.
- Neural stem cells (brain)
With reduced neurogenesis (new neuron formation), memory declines.
- Hair follicles
Hair can stop growing and become thin.
- Mesenchymal stem cells (bone)
Bones are constantly adapting to stress and being remodelled. If bone formation cannot keep up with bone breakdown, the risk of osteoporosis and stress fractures increase.
Slowing stem cell exhaustion
It is hypothesized that if a hallmark of aging can be ameliorated (i.e. if stem cell function can be restored), the aging process can be slowed, stopped, or even reversed. The discovery of such an anti-aging drug would be extremely profitable, and this has created the conditions for profit-driven research models, rushed experiments and patenting, false claims and overhype. It is unlikely there will be a one-drug solution to biological aging. Although some therapeutic interventions have shown promise in animals, they are still experimental in humans.
The most studied longevity drugs target pathways, such as mTOR and AMPK. mTOR inhibitors, such as rapamycin, may stimulate autophagy and maintain stem cell function. Signs of aging accumulate as cells divide and grow, and mTOR is a growth signal, so the theory is that inhibiting it will prioritize maintenance and repair overgrowth and reproduction, thereby slowing aging. Although rapamycin has been studied in small clinical trials and is regularly used off label, there haven’t been any large, long-term randomized controlled trials confirming its anti-aging effects in humans. Unlike mTOR, AMPK signals repair and recycling, so compounds that activate it, such as metformin or Berberine, interest researchers and biotech companies. Metformin has been widely studied for type 2 diabetes, but its aging-related outcomes are still developing.
NAD+ boosters, sold as capsules, powders, IVs, injections, drinks, etc., are trending in the mainstream wellness world, hitting US$3.4B sales globally in 2024. NAD+ is an essential coenzyme that helps make energy and repair DNA. It declines as we age, but consuming or injecting it doesn’t necessarily increase lifespan.
There is also a class of drugs known as senolytics. Senolytics kill senescent cells, which are “zombie cells” that no longer divide but release inflammatory signals. It is thought that this will slow aging, and animal trials show compounds like quercetin and fisetin may improve stem cell function. Despite the buzz around senolytics, further research on humans is needed.
Yamanaka factors are genes that can reset a mature cell back into an embryonic-like state, creating induced pluripotent stem cells (iPSCs). The man who identified these genes, Dr. Shinya Yamanaka, won a Nobel Prize for his discovery because it showed mature cells can be fully reprogrammed, which might not just slow aging, but could reverse it. iPSCs can regenerate tissue but, unfortunately, Yamanaka factors aren’t without risks, such as uncontrolled cell growth and cancer.
Many lifestyle interventions have gained traction in the wellness world, such as caloric restriction and exercise. One of the most validated ways to increase longevity is caloric restriction. Eating less inhibits mTOR, activates AMPK, and increases autophagy. But, over time, it can also lower muscle mass and disrupt hormones. Exercise – arguably one of the most powerful aging interventions for humans – has been shown to lower the risk of death. It reduces inflammation, supports stem cell function, promotes neurogenesis, and improves brain health. Unfortunately for investors, lifestyle changes like exercise have the most evidence in humans but aren’t patentable.
Today, billions of dollars are invested in longevity research. However, commercial incentives can lead to misinformation and the overstatement of findings. It is important to be cautious when it comes to products that claim to increase lifespan or reverse aging. Exciting research in the past three decades has shown that it is possible to do so, but human trials are still being conducted.
Ellie Kroeger
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