Disclaimer: this article is for informational purposes only and does not constitute medical or wellness advise. For any medical questions or issues, or the use of any prescription drugs, please contact your healthcare practitioner.

The ancient chase after eternal life, from the epic of Gilgamesh to the Adventures of the Explorers and Conquistadors, is a constant companion, as old as recorded history itself. Alas, the chase has fundamentally shifted from the wild journeys into the "faraway" or distant seas and reverted into an inward-looking microscopic and nanoscopic journey to understand the inner workings of living cells, and the distant lands and seas have been replaced with microscopes and lab benches.

The journey turns inwards

Nowadays, it is clear that unless you are approaching the speed of light or orbiting a massive black hole, journeying and wandering are unlikely to add many years to your expected lifespan. Instead, the secrets to a long and healthy life lie deep within us. "Know thyself" is totally the zeitgeist of our time, and this holds true both on the biological and individual levels, as the unprecedented insights into human biology to the deepest molecular level can only serve us best when we reflect on our individual lifestyle, habits, personal needs, and, of course, our unique genetic package.

But how and when did the long, fantastical chase after eternal youth morph into the measurable, quantifiable, and actionable science of longevity biology? When did the unattainable legendary immortality give way to the science-based endeavors of gerontology and longevity?

Life expectancy and longevity: two entirely different things

Here it helps to start with what is often mistaken as longevity but is not, which is the massive improvement in health and life expectancy through the second half of the 20th century. It was mostly sanitation, antibiotics, and vaccines that added over 25 years to the global life expectancy. The earlier drastic improvements are mostly attributable to the reduction in early childhood death, maternal death at birth, and death due to sepsis following various operations. More recently, advances in managing chronic conditions, including coronary and cardiac diseases and diabetes, continue to contribute incrementally to an increased life expectancy, which will approach 6 additional years by the mid of this century, to reach 76 years. To put this in perspective, life expectancy at birth was a mere 31 years. However, anyone celebrating their 45th birthday alive could, on average, look forward to an extra 20 years of healthy living. This means that notwithstanding all the improvements in averting earlier death, the entire technological and civilizational advancement has barely added 10 years to the average life expectancy and not much more to what is originally biologically possible. For example, being born in the 17th century, Isaac Newton reached 84 years of age, and Cato the Elder—almost two millennia earlier—is thought to have seen his 85th birthday.

In short, the unprecedented understanding of biology down to the cellular and molecular level, combined with breath-taking technological advancement, has yet to show its actual effect on human life expectancy. The fields of gerontology and longevity research focus on harnessing biological and technological advancement to specifically target aging as a disease so as to delay morbidity and mortality proactively and prophylactically by halting or reversing the processes that precipitate cumulatively in our cells, tissues, and organs as we age, the so-called hallmarks of aging.

Calorie restriction: the first and benchmark of longevity interventions

Hereon further, we will briefly explore the beginnings and basic principles of the brilliant and ever-young field of longevity biology, starting with the immediate promise of reaching a century in good health, up to the wild potential of multiple-century life and making death optional.

Almost a century ago, calorie restriction (CR) emerged as the first quantifiable and reliable way of extending the lifespan of multiple species, including humans. In 1935, McKay and his colleagues simply and elegantly demonstrated meaningful increases in the lifespan of rats in response to the reduction of food (calorie) intake, as opposed to ad-libitum feeding, while maintaining the intake of all essential nutrients to prevent malnutrition. In fact, calorie restriction remains the standard of life extension interventions and has communities of enthusiasts that have made a lifestyle around it. Intriguingly, ancient wisdom in Okinawa, one of the centenarian Blue Zones I tackled in a previous article, has long intuitively identified calorie restriction as a useful intervention, as embodied in their "hara hachi bu" concept.

Growth and lifespan

The initial hypothesis was built upon a hypothetical link between growth and lifespan. Indeed, there is much evidence across species that links growth reductions to a longer and healthier life. For example, smaller dog breeds are known to survive longer, with average lifespans between 12 and 16 years, compared to 8 to 12 years for larger dogs. This is a whopping difference of 50%, as dogs make for the perfect species for observing such differences due to the huge size variation between breeds.

Nonetheless, height correlates inversely with lifespan in humans as well, and mutations in the growth hormone receptor that render it less effective are among the genetic variations most observed in centenarians, offering further mechanistic proof beyond the basic circumstantial observation. This remarkable question poses a vital one, one that probes the relationship between growth and lifespan?

Rapamycin, an enigmatic molecule

The initial clues to the answer were first provided by a very unlikely agent, whose serendipitous discovery on the Island of Rapa Nui (Aka. Easter Island), one of the remotest spots on earth, upended our understanding of how cells orchestrate hundreds of pathways to simultaneously support growth and basic energy requirements. Rapamycin, named after the island, is made by the bacterium Streptomyces hygroscopicus to monopolize the environment by preventing competition by fungal species. Bacteria and fungi, in many ways, are more different than fungi and humans on the cellular level. For instance, fungi, just like all mammals, including us, have a cell nucleus separating their genomic DNA from their cytoplasm, while bacteria lack such compartmentalization.

Rapamycin was first investigated as a promising anti-fungal agent. But soon it turned out to have more significant superpowers in inhibiting cell growth and proliferation. The designation as an immunosuppressant for organ transplant patients has long eclipsed the versatile potential of this molecule. Nonetheless, the work on longevity has identified rapamycin as the most successful drug in promoting lifespan in all tested eukaryotic organisms, from yeast to mice, and improving health span in humans, including immune response.

The target of Rapamycin: a cellular growth switch

The effectiveness of rapamycin across species highlighted a common evolutionarily conserved mechanism. Fascinatingly, the study of its mechanism led to the identification of its eventual target, TOR (long form: target of Rapamycin) in yeast and mTOR (mammalian "or mechanistic" target of Rapamycin).

This is an exciting example of a drug with observed effects leading to the discovery of its own target, contrary to the usual drug discovery pipeline that usually begins with identifying the target. The target had eluded researchers until discovered by David Sabbatini and his colleagues, who also continued to discover the natural cellular mechanisms of mTOR activation and describe its downstream signalling.

Part of the elusiveness of mTOR is the versatility of its signalling in the cell, as it upregulates all anabolic pathways, including protein synthesis, processes that were long neglected as "housekeeping" or "constant" functions in the cell.

Calorie restriction mimetics

Rapamycin, as a longevity drug, is a prominent calorie restriction mimetic, as it exerts similar effects by binding and inhibiting the growth signalling mediated by its target. Indeed, the mechanism is common to calorie restriction, as mTOR activation happens in response to nutrients, especially amino acids, released in specialized cellular compartments called lysosomes as the product of breaking down proteins. Consistently, protein restriction in particular yields the strongest mTOR suppression.

Since calorie restriction is very challenging to implement in our day and age, the search for other mimetics has been fervent. Many mimetics have been discovered, and these include natural interventions such as intermittent fasting, which still gives comparable results even while the overall calorie intake is preserved, in addition to other drugs that mimic calorie restriction.

Metformin and AMPK: another calorie restriction mimetic

Among these drugs, for instance, is metformin, a very popular type 2 diabetes medication, which is also found to have positive effects on improving health, with some preliminary evidence for life extension.

At the core of metformin's mechanism of action is the inhibition of mitochondrial complex I. The mitochondria are the power plants of all eukaryotic cells, and they produce the major type of fuel for use in the cell called ATP. By inhibiting mitochondrial complex I, the cellular ability to produce ATP from nutrients is hampered, and a byproduct of this is AMP, which then turns on another cellular switch called AMPK. First described by Hawley and colleagues, AMPK has been identified as the off-switch for cellular growth and proliferation.

AMPK and autophagy: cellular repair and maintenance

Starvation induces AMPK to preserve the cells by preserving the scarce energy needed for cellular homeostasis. It also turns on another mechanism called autophagy. Greek for "eating self," this process allows the cell to recycle its inner components, including proteins and organelles. This fascinating process was discovered by Nobel laureate Yoshinori Ohsumi.

Autophagy selectively recycles the most damaged and faulty parts of the cell, hence offering a quality-check mechanism for cellular maintenance and repair.

mTOR and AMPK: the switch and nexus of cellular growth and energy regulation

Together, mTOR and AMPK, with their respective downstream signalling, provide an on/off switch to cellular growth and proliferation that is naturally controlled by the availability of nutrients. Decades of searching for cellular longevity secrets uncovered this nexus of cell signalling as the major controller of cellular and organismal longevity and survival.

Intriguingly, calorie restriction and fasting have been an involuntary constant companion of our hunter-gatherer ancestors as they were subjected to periods of food scarcity. Evidence suggests that protein, especially, was difficult to come by, and hence, periods of protein abstinence were a natural part of life. This showcases another brilliant example of the adaptation of basic cell biology to natural environmental cues.

The discovery of cellular growth and energy metabolism switches is just the beginning of a long battle against death. While the upcoming technologies of gene and cell therapy, cell reprogramming, and synthetic biology are likely to enable radical life extension, the optimization of our nutrition and metabolism, and ensuring that our cells and organs get the essential levels of self-repair and maintenance to enable a longer and healthier life.

Note: If you enjoyed reading this brief story of basic longevity interventions, I would strongly recommend a book called "The Switch" by James Clement and two podcast episodes by Dr. Peter Attia, in which he dissected Rapamycin and mTOR signalling with David Sabatini and Matt Kaeberlein.

References

1 The Changing Landscape of American Life Expectancy.
2 Life Expectancy in Hunter-Gatherers. McCauley, B. (2019). Life Expectancy in Hunter-Gatherers. In: Shackelford, T., Weekes-Shackelford, V. (eds) Encyclopedia of Evolutionary Psychological Science. Springer, Cham.
3 Honoring Clive McCay and 75 Years of Calorie Restriction Research. McDonald RB, Ramsey JJ. Honoring Clive McCay and 75 years of calorie restriction research. J Nutr. 2010 Jul;140(7):1205-10. doi: 10.3945/jn.110.122804. Epub 2010 May 19. PMID: 20484554; PMCID: PMC2884327.
4 Surendra Nath Sehgal A pioneer in rapamycin discovery. Samanta, Debopam. Surendra Nath Sehgal: A pioneer in rapamycin discovery. Indian Journal of Cancer 54(4):p 697-698, October–December 2017. | DOI: 10.4103/ijc.IJC8418.
5 Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Sabatini DM. Twenty-five years of mTOR: Uncovering the link from nutrients to growth. Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11818-11825. doi: 10.1073/pnas.1716173114. Epub 2017 Oct 25. PMID: 29078414; PMCID: PMC5692607.
6 Metformin: A Hopeful Promise in Aging Research. Novelle MG, Ali A, Diéguez C, Bernier M, de Cabo R. Metformin: A Hopeful Promise in Aging Research. Cold Spring Harb Perspect Med. 2016 Mar 1;6(3):a025932. doi: 10.1101/cshperspect.a025932. PMID: 26931809; PMCID: PMC4772077.
7 AMP-activated protein kinase—an energy sensor that regulates all aspects of cell function. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011 Sep 15;25(18):1895-908. doi: 10.1101/gad.17420111. PMID: 21937710; PMCID: PMC3185962.
8 The Nobel Prize in Physiology or Medicine 2016.
9 The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism. Zhang, Chen-Song et al. “The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and mTORC1, acting as a switch between catabolism and anabolism.” Cell metabolism vol. 20,3 (2014): 526-40. doi:10.1016/j.cmet.2014.06.014.