Pharmacological Approaches to Longevity (Part 2)

In the first part to this article, we considered a key ‘biohacking’ approach to extending our longevity that involved the mTOR pathway. Today, we’ll be exploring two other approaches that seek to tweak our biological ageing process by other pharmacological methods. Then, in the next article, 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.

Back to the Future: A 2,000-year Old View of Ageing

The concept of ageing as an inherent process in our biology is a longstanding one. Back in the days of ancient Greek civilisation, famed physician Galen framed ageing as a natural process whose “causes of destruction” were present “innately from the beginning”[1]. Based on our biological understanding at present, this is still largely true - maturation followed by ageing seems to be a multi-pronged process characterised by physiological changes[2]. 

Today, advances in scientific methods have enabled us to have a more granular understanding of the biology of ageing. In this article, we’ll feature various pioneering cellular biology approaches, all with the aim of extending our longevity.

Mitochondrial Regulation: Empowering Our Cells’ Powerhouses

Mitochondria are the cells’ ‘powerhouses’, for they act as sites for respiration in order to produce the energy currency for cells. On a cellular level, they have been found to play a key role in the ageing process - for instance, studies have shown that ageing and its associated cognitive decline may be correlated with a decrease in mitochondrial enzyme function[3]. 

In addition, another noteworthy point is that mitochondria contain their own DNA separate from the DNA in our cells. In other words, each cell contains a nucleus where DNA e.g. coding for our hair and eye colour can be found, but the same cell also contains mitochondria which in turn holds mitochondrial DNA. Interestingly, animal models which are engineered to be deficient in their ability to repair mitochondrial DNA exhibit signs of premature ageing, which suggests that mitochondria play an instrumental role in ageing[4]. 

With the above in mind, startups such as Nanna Therapeutics are harnessing the power of science to alter mitochondrial biology in a bid to achieve greater longevity. With a focus on targeting age-related diseases, Nanna is working on a drug discovery system to identify compounds which could promote healthier mitochondria even as one ages. Amongst other capabilities, their drug discovery approach combines microfluidics, nanoscale synthesis of chemical libraries (for potential drug compounds) and artificial intelligence[5]. Taken together, these capabilities could shorten the time it takes for suitable mitochondria-targeting, longevity-promoting drug compounds to be identified and subsequently tested. 

Whilst a lifespan-extending drug targeting our mitochondria may be some time away from the clinic, mitochondrial medicine is an exciting area to keep tabs on. To follow Nanna Therapeutics’ work, check out their website at: https://www.nannatherapeutics.com/

Senescent Selection: Out with the Old, In with the New

Aside from mitochondrial changes, our cells also become senescent as we age. The term “senescence” derives from the Latin “senex”, meaning old[6], and is synonymous with biological ageing in today’s parlance. Why do cells become senescent, one may ask? Whilst it may seem counterintuitive, senescence can have protective effects as it is “a key cellular program that...plays an important role in permanently restricting the propagation of damaged and defective cells”[7]. How this happens is that when cells become senescent, there is a halt or an “arrest” in the cell cycle, meaning that the rate at which cells divide slows and eventually stops[8]. Why might this be a problem in terms of ageing? The key revolves around a body of evidence that, in the process of senescence, biological changes such as inflammation occur, resulting in a cascade of ageing-related diseases such as osteoarthritis[9].

In a bid to extend longevity whilst remaining healthy, an emerging biopharma approach involves the selective elimination of senescent cells, also known as senolytics. A pioneering company in this field is Unity Biotechnology, whose initial focus is on delivering localized therapy in osteoarthritis, ophthalmology and pulmonary disease. In a paper titled “Senolytic Therapies for Healthy Longevity”, Unity explains how their drug technology promotes apoptosis or cell death of senescent cells in a targeted manner, such that only senescent cells are removed - healthy cells, in the meantime, are not affected[10]. 

Whilst “localised” diseases such as eye diseases and osteoarthritis form Unity’s immediate therapeutic focus, a diagrammatic representation of their technology also suggests the possibility of “systemic senolysis” in the future. Possible indications could include systemic ageing-related diseases such as neurodegeneration and coronary obstructive pulmonary disease amongst others.

To find out more about Unity’s exciting pipeline development, follow their updates on: https://unitybiotechnology.com/.

Conclusion

In this two-part article on pharmacological approaches to longevity, we started off by exploring the extension of our lifespans by “hacking” the mTOR pathway via dietary restriction and medicines to inhibit the pathway. Then, we turned to targeting our mitochondria - the powerhouses of our cells - and the selective elimination of old or senescent cells. These novel approaches pushing the frontiers of biological ageing represent the possibility that one day, perhaps in the not-so-distant future, Galen’s “causes of destruction” which were present “innately from the beginning” may form the basis of effective treatments for greater longevity.

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

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[2] Lopez-Otin, C. et al (2013) The Hallmarks of Ageing, Cell, retrieved October 29th, 2019 from https://www.cell.com/action/showPdf?pii=S0092-8674%2813%2900645-4

[3] Navarro, A. (2004) Mitochondrial Enzyme Activities as Biochemical Markers of Ageing, Molecular Basis of Medicine, 25: 1-2, retrieved October 29th, 2019 from https://www.sciencedirect.com/science/article/pii/S0098299704000081?via%3Dihub

[4] Kujoth, J.C. et al (2005) Mitochondrial DNA Mutations, Oxidative Stress, and Apoptosis in Mammalian Ageing, Science, 15: 309, retrieved October 29th, 2019 from https://science.sciencemag.org/content/309/5733/481.long

[5] Nanna Therapeutics (n.d.). Nanna Therapeutics - Technology, retrieved October 29th, 2019 from https://www.nannatherapeutics.com/ 

[6] Merriam Webster Dictionary, (n.d.), retrieved October 29th, 2019 from https://www.merriam-webster.com/dictionary/senescence#targetText=Senescence%20can%20be%20traced%20back,senex%2C%20meaning%20%22old.%22&targetText=There's%20also%20the%20much%20rarer,of%20the%20normal%20life%20span)

[7] Bolden, J. E. and Lowe, S. W. (2015). Chapter 15: Cellular Senescence. In The Molecular Basis of Cancer, 4th Ed. (pp 229-238), Saunders

[8] Hernandez-Segura, A. et al (2018). Hallmarks in Cellular Senescence, Trends in Cellular Biology, 28:6, retrieved November 23rd, 2019 from https://www.cell.com/trends/cell-biology/fulltext/S0962-8924(18)30020-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0962892418300205%3Fshowall%3Dtrue

[9] Lasry, A. and Ben-Neriah, Y. (2015). Senescence-associated Inflammatory Responses: Ageing and Cancer Perspectives, Trends in Immunology, 36:4, retrieved November 24th, 2019 from https://doi.org/10.1016/j.it.2015.02.009 

[10] van Deursen, J. (2019). Senolytic Therapies for Healthy Longevity, Science, 36:6441, retrieved November 24th, 2019 from https://unitybiotechnology.com/wp-content/uploads/JVD-Perspective-Science.pdf