Pharmacological Approaches to Longevity (Part 1)
This series of articles on longevity seeks to explore four key aspects to living longer. In the first article, we considered various digital approaches that address the many facets of longevity. In this two-part article, the question turns to extending that longevity: might it be possible to increase our lifespan, and what are some pharmacological approaches currently in the pipeline? Then, we’ll take a look at the proposition that longevity is relative - living till the ripe old age of 80 may be something that most of us can look forward to, whereas reaching the age of 30 may be a luxury for those living with rare diseases. Finally, we’ll consider a broader perspective on how societal design changes can keep up with our ever-increasing longevity.
Our Continuing Quest for Longevity
From the philosopher’s stone to the fountain of life, finding an “elixir of life” has long been at the forefront of Mankind’s quest for eternal living. Through the years, our desire for greater longevity has led us to push the boundaries of ageing in innovative ways.
Today, advances in our understanding of biological mechanisms have made us look to science for potential ways to extend our lifespans. Here, we feature the evolution of various pioneering approaches that could bring us one step closer to making this a reality.
Hacking Our Biology: Longevity’s ProtecTOR?
Steven Johnson, science author and media theorist, once said, “If you look at history, innovation doesn’t come just from giving people incentives; it comes from creating environments where their ideas can connect”. This profound statement rings true where it comes to “hacking” into the basics of our biology to extend our longevity.
Back in the 1990s, two seemingly disparate scientific and regulatory advances were made. The first relates to the FDA’s approval of rapamycin, a drug that suppresses the body’s immune response in patients who have undergone organ transplantation[1]. The second relates to the study of biological pathways in yeast on a molecular level.
How might immunosuppression and yeast biology have anything to do with ageing, one might ask? Indeed, these two superficially unconnected developments were weaved together by a common thread when a team led by Michael Hall discovered that yeast treated by rapamycin seemed to live longer[2]. The team found that this was because rapamycin, aside from having an immuno-suppressive effect, mimicked starvation in cells by acting on a biological pathway called the mTOR pathway[3].
The mTOR pathway is an important signaling cascade whereby a series of chemical reactions takes place at the cellular level - think of a stack of dominoes where each domino that tips over causes the next one to fall. Interestingly, an emerging body of evidence reveals that mTOR is implicated in various physiological processes, from ageing to immune maintenance and nutrient control. When the mTOR pathway is dysregulated, health problems that pose a challenge to longevity can occur, such as cancer and diabetes[4].
Armed with the above knowledge, researchers have sought to “hack” the TOR pathway to enhance longevity by two main methods: 1) dietary restriction, and 2) inhibiting the TOR pathway to boost the elderly’s immune responses.
Dietary Restriction
As the mTOR pathway has been conserved even through the sands of time and evolution, this pathway is present in various types of organisms, from yeast to flies, nematodes, and humans. Thus, results obtained from studying animal models in the lab may help us understand more about the mTOR pathway in humans.
Interestingly, scientists have found that dietary restriction reduces mTOR signaling - a simplistic analogy would be turning down the volume on the radio[5]. Reduced mTOR signaling seems to have beneficial effects - for instance, this activates cellular repair machinery, allowing old or damaged cells to repair themselves. This seems to slow down the ageing process, leading to longer lifespan in lab animal models.
What, then, are the implications for translating these research results into actionable plans for extending our lifespans? Whilst results may look promising, we perhaps ought to throw caution to the wind. Afterall, ageing is a multifactorial process[6], such that other biological pathways beyond mTOR are likely to play a role. Furthermore, as Johnson et al noted with regard to diet limitation, “interpretation of these types of experiments is complicated by the fact that several different dietary restriction protocols are used, and quantitative assessments of activity are often missing”[7].
In a nutshell, whilst the use of dietary restriction as a means of increasing our longevity is an exciting space to keep a lookout for, more definitive evidence of a link between caloric restriction and longevity would probably be needed to warrant tweaking our diet plans.
Immune Responses
As briefly explained above, mTOR affects a multitude of biological processes, including immune function and inflammation. Leveraging on the growing body of research on mTOR’s immunomodulatory effects, Novartis and PureTech spun out reSTORbio, a biotech that focuses on targeting the mTOR pathway for ageing-related diseases[8]. Specifically, reSTORbio is currently investigating the use of a drug to inhibit the mTOR pathway, and measuring the effect of such blocking on better immunity in the elderly.
According to a recent company presentation, targeting the mTOR pathway led to stronger antiviral immunity, resulting in fewer instances of respiratory tract infections (RTIs) in the elderly[9]. This is an exciting finding as respiratory tract infections are one of the main causes of mortality in the elderly. By boosting our immune systems even as we age, this reduces our susceptibility to infections such as RTIs, likely contributing to greater longevity.
Conclusion
To sum it up, altering the mTOR cascade - an important biological pathway - is one of several pharmacological means that could potentially lead to greater longevity, although more definitive evidence would likely be necessary before mTOR therapeutics takes root in the clinic. In the second instalment to this two-part article, we’ll look at other pharmacological methods which could extend our lifespan, namely - tapping on our cells’ powerhouses and the selective removal of old cells.
Zera is passionate about the intersection between biotech therapeutics and digital health, is a trustee at Shift.ms (a multiple sclerosis charity) and also leads research lectures at Parkinson’s UK. In the upcoming Horasis 2020 conference, she will be speaking on the longevity panel.
Disclaimer: This article has been written in Zera’s personal capacity. All opinions expressed in this article are the author's own and do not reflect the view of her employer nor of any affiliated organisations.
Sources and Bibliography
[1] Approval Package for Rapamune Oral Solution (1999) Centre for Drug Evaluation and Research, retrieved October 17th, 2019 from https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A_Rapamune_appltr.pdf
[2] Connor, A.N. (March 1st, 2018) Could Rapamycin Help Humans Live Longer? The Scientist, retrieved October 17th, 2019 from https://www.the-scientist.com/notebook/could-rapamycin-help-humans-live-longer-30021
[3] Hall, M. (1996) The TOR Signalling Pathway and Growth Control in Yeast, Biochemical Society Transactions, 24 (1), retrieved October 17th, 2019 from https://portlandpress.com/biochemsoctrans/article/24/1/234-239/88753
[4] Bar-Peled, L. and Sabatini, D.M. (2014) Regulation of mTORC1 by Amino Acids, Trends Cell Biology, 24 (7), retrieved October 21st, 2019 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074565/
[5] Johnson, S.C. et al (2013) mTOR is a Key Regulator of Ageing and Age-related Disease, Nature, 493 (7432), retrieved October 21st, 2019 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687363/#R19
[6] Lopez-Otin, C. et al (2013) Hallmarks of Ageing, Cell, 153:6, retrieved October 21st, 2019 from https://www.cell.com/fulltext/S0092-8674(13)00645-4
[7] ibid, 5.
[8] PureTech Health Announces Licensing and Equity Agreement with Novartis to Advance Clinical Stage mTORC1 Programs (March 24th, 2017), retrieved October 21st, 2019 from
[9] ReSTORbio (2019) Targeting the Biology of Ageing to Prevent and Treat Ageing-related Diseases, retrieved October 21st, 2019 from https://ir.restorbio.com/static-files/a881eb25-bbc9-4090-8f0b-7582aa7d3246