In Search of the Holy Grail
Would you choose to live forever? And, more importantly, can you? The quest to slow ageing is possibly the oldest pursuit in medical research, with ancient societies trialling remedies such as alchemy, curative waters and drinking gold (which was of course toxic). For good reason, the question of whether we can create an elixir of life has been a controversial one in the scientific community. Anti-ageing medications have been brought to market without evidence that they work in humans1, and other treatments have caused lab animals to grow ‘teratomas’ (terrifying cancers which can contain teeth, hair and bone; google if you feel brave…). While many medical organisations still do not recognise anti-ageing medicine, a growing number of scientists (and billionaires) believe we may be mere years away from the development of a pill to treat ageing.
But what does ‘anti-ageing’ actually mean?
Without a doubt, advances in medicine and public heath have radically improved life expectancy. However, this quality of life is poor, with 74% of people globally dying from diseases of ageing, such as cancer, cardiovascular disease and dementia2. Thus, the focus of anti-ageing research is not to increase lifespan, but instead ‘healthspan’. The ‘geroscience hypothesis’ proposes that by treating the physiological signs of ageing we will consequently cure related diseases. Simultaneously, we may also curb cosmetic features associated with getting older, which is a nice little bonus.
Various mechanisms in cell biology contribute to the ‘hallmarks of ageing’3. Firstly, throughout our lives our cells are constantly dividing. While this keeps us alive, replicating cells accumulate mutations in their DNA; the longer we live, the more our cells must divide and the more genetic mutations we accrue. These mutations disrupt the normal functioning of our cells and are best known for their cancerous properties.
While our genes serve as the instructions for how our cells behave, our epigenetics dictate which genes are ‘read’. It’s this phenomenon which allows all the cells in our body to have the same genetic sequence but to look and act completely differently. As we get older, we develop ‘epigenetic drift’, which leads to aberrant cell behaviour.
The vulnerable ends of our genome are protected by extra pieces of DNA called telomeres. As our cells divide telomeres get shorter, eventually triggering cell death by ‘senescence’. Senescent cells release damaging chemicals and immune senescence leads to chronic inflammation, both of which promote ageing. Furthermore, older tissues become depleted of stem cells, which are required to replace dying cells, causing both senescent cells and DNA damage to amass.
One of the best evidenced longevity boosters is dietary restriction (Twitter CEO Jack Dorsey fasts for 22 hours a day). Unsurprising then, that deregulated nutrient sensing is a hallmark of ageing. Nutrient level is detected by specific proteins in our cells, which in response mediate changes in cell growth, immune function and metabolism. The nutrient-sensors, and many other systems in our body, participate in cell-to-cell communication. As we get older, these networks malfunction, contributing to development of diseases like type 2 diabetes and atherosclerosis. Another trait of ageing is central to the development brain disorders such as Alzheimer’s disease. This ‘failure of proteostasis’ is characterised by protein misfolding and an imbalance in protein abundance.
Finally, mitochondria, the energy-producing centres of the cell, produce ‘reactive oxygen species’ (ROS), which were initially thought to drive ageing. However, this has since been contested, and ROS may in fact promote longevity. However, dysfunctional mitochondria still contribute to ageing through regulation of cell death and inflammation.
All sounds pretty inevitable…
Indeed, our chance of dying doubles every eight years, making many scientists predict a maximum age of around 120 years4. However, some animals are luckier. When the Galapagos tortoise and species of BOFFFF (big, old, fat, fertile, female fish, not joking), reach a certain age they enter ‘negligible senescence’ and their chance of dying plateaus5. Which means they could live forever, right?
So, if them, why not us?
At this point, you might have guessed one anti-ageing strategy is to target senescence. Indeed, senolytics (which remove senescent cells) and senostatics (which quell the effects of senescent cells) are the focus of many startups, but have not yet shown efficacy in clinical trials6. Partial cellular reprogramming is another approached favoured by Silicon Valley moguls such as Jeff Bezos. The discovery of Yamanaka factors and their ability to restore a cell to its younger epigenetic state won Shinya Yamanaka the 2012 Nobel Prize. However, this approach is tricky; exposing cells to these factors for too long can lead to the development of those nasty teratomas. It’s likely that other genes involved in cell reprogramming will need to be found, with Google’s Calico Labs admitting that research on Yamanaka factors is “not something where we’re thinking clinically”7.
One of the more gruesome methods to slow ageing is a transfusion of babies’ blood. The startup Ambrosia sold adolescent blood transfusions for $8000 a litre (or grab yourself a bargain with $12000 for two) until it was shut down by the FDA in 20198. However, parabiosis has been shown to reduce age-associated inflammation, increase stem cell capacity and even improve neurological function. Faecal transplants may similarly benefit older patients; transfer of the gut microbiome can improve nutrient sensing and weight regulation. Existing drugs metformin, a diabetes medication, and rapamycin, an anticancer compound, could be repurposed to treat ageing, again through targeting our nutrient sensing systems. Rapamycin has already shown some promise in the 2020 Dog Ageing Project (possibly the cutest ageing trial so far)9.
The above examples represent just a trickle of the many avenues being explored in the race to cure ageing. With a treatment potentially around the corner, is it time to rethink our views on the inevitability of getting older? And which therapy has your backing? Or maybe we should just take the advice of the oldest human in history, 122-year-old Jeanne Calment: she attributed her longevity to cigarettes and chocolate.
References
- Callaway, E. GlaxoSmithKline strikes back over anti-ageing pills. Nature (2010). doi:10.1038/news.2010.412
- World health statistics 2021: monitoring health for the SDGs, sustainable development goals. (2021).
- López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The Hallmarks of Aging. Cell 153, 1194–1217 (2013).
- Finch, C. E. & Pike, M. C. Maximum Life Span Predictions From the Gompertz Mortality Model. Journals Gerontol. Ser. A 51A, B183–B194 (1996).
- Finch, C. E. Variations in Senescence and Longevity Include the Possibility of Negligible Senescence. Journals Gerontol. Ser. A 53A, B235–B239 (1998).
- Dolgin, E. Send in the senolytics. Nat. Biotechnol. 38, 1371–1377 (2020).
- Eisenstein, M. Rejuvenation by controlled reprogramming is the latest gambit in anti-aging. Nat. Biotechnol. 40, 144–146 (2022).
- Corbyn, Z. Could ‘young’ blood stop us getting old? The Observer (2020).
- Partridge, L., Fuentealba, M. & Kennedy, B. K. The quest to slow ageing through drug discovery. Nat. Rev. Drug Discov. 19, 513–532 (2020).
About the author: Amy Stainthorp is a post-doctoral researcher using 3D cell systems to study Barrett’s oesophagus at the University of Leeds. She work in Professor John Ladbury’s group and as part of the Leeds Centre for Disease Models. She recently completed her PhD investigating the regulation of microRNA expression at the University of Leeds.