Fight Aging!

I recently noticed an academic conference report covering the Longevity Med Summit held last year in Portugal. More organizers should put out commentary papers after the event; the only downside is that it takes far too long to move from writing to publication, as illustrated by the year-long delay here. It is good to see more events held in Europe these days, and more conferences setting out to explore a different part of the sizable space of research, industry, and clinics. I'm not going to comment on the conference series, but rather use it as an opportunity to note that all too much of the longevity field is focused on initiatives that are unlikely to make all that much difference.

Most companies develop small molecule drugs. Most small molecule drugs developed to target aging are in some way manipulating metabolism to slow aging, or compensate for some specific effect of aging. Most have most modest effect sizes, and only capture a small fraction of the results of the mutations or gene therapies that inspired them. Small molecule development has the advantages of being well-understood, involves lower costs, and offers a good amount of drug repurposing opportunities (again, lower costs), among others. It has the glaring disadvantage of turning out drugs that only modestly affect the target issue. The ever-more-costly machinery of the FDA spends most of its time attempting to tell the difference between marginally beneficial small molecules and useless small molecules.

Are we really all supporting this process of developing a longevity industry in order to call it a success to take an existing drug and repurpose it to gain a couple of years of additional life expectancy? That doesn't really change the big picture at all. It doesn't put a meaningful dent in the fundamental problem, that we are aging and dying. Yet it seems we might be doing just this, given the behavior of many of those involved. Setting aside the present fervor for reprogramming, the investment in marginal small molecule therapies - and number of companies involved in that work - outweighs the lesser number of groups working on potentially impressive approaches such as mitochondrial transplantation and advanced senolytics.

The Longevity Med Summit: insights on healthspan from cell to society

Translation of academic findings into practical applications within industry and clinical context is of the utmost importance within the field of longevity. The hallmarks of ageing have played a key role in paving the way for providing mechanisms for therapeutics to target and modify them for lowering biological age and enhancing longevity, attracting interest from academia, industry, and investors. Several speakers presented various data on the pharmacological and nutraceutical interventions currently under investigation in clinical trials, or in the pipeline.

Metformin and rapamycin, and its analogues (rapalogs), are among the most extensively studied longevity compounds, targeting AMPK and mTOR, respectively, as discussed by multiple speakers. Repurposing existing drugs has shown promise in combating ageing. These compounds exhibit a range of beneficial effects, including immunomodulation and alteration of cellular metabolism mechanisms, in both in vitro and in vivo models of healthy ageing. However, for their prescription solely for longevity purposes, further research is warranted to determine appropriate dosages and potential impacts on other bodily systems.

In addition to repurposing existing drugs, there are ongoing efforts to identify novel compounds and devise effective therapeutic regimes using machine learning and network pharmacology. Longevity and ageing research has necessitated a shift in disease research from reductionist to systems theory. Joao Pedro Magalhaes (University of Birmingham) discussed his research and the emergence of network pharmacology and in silico models, incorporating various disciplines such as systems biology, genomics, and proteomics, among others. By examining drug-network interactions through omics data analysis and network database retrieval, network pharmacology provides comprehensive insights into drug mechanisms and efficacy, making it particularly suitable for investigating longevity therapeutics.

A growing array of supplements, such as NAD+ and its precursors for cellular energy, calorie restriction mimetics for fasting-like effects, and other bioactives and nutraceuticals, are being explored for their potential anti-ageing benefits. These compounds target specific pathways or provide broad antioxidant and anti-inflammatory properties, which can alleviate age-related damage and promote overall health. Despite being promoted by numerous commercial entities, clinicians may exhibit hesitancy due to less stringent regulatory processes.

At the cellular level, senolytics are a class of drugs that aim to interfere with senescent cells. Several speakers outlined the process of cellular senescence and its contribution to unhealthy ageing via mechanisms including disrupting tissue functionality and limiting the regenerative potential of adult stem cells. The accumulation of senescent cells leads to an increase in biological age and increases the risk of disease. Senolytics hold promise in eliminating senescent cells, and in model organisms, they have shown potential to extend lifespan, enhance healthspan, and treat or even reverse age-related diseases.

Advancing to the systemic level, dysbiosis and chronic inflammation, recently recognised hallmarks of ageing, are interconnected and responsive to dietary interventions, as elucidated by Richard Siow (King's College London). Bioactive compounds in whole foods, potentially acting synergistically to mitigate age-related changes and enhance vitality pathways, are currently being investigated by commercial entities to isolate and validate them in vivo. Siow also emphasised the significant impact of dietary choices on rates of functional decline. With the emergence of longevity nutrition frontiers such as nutrigenomics, personalised nutritional regimens tailored to individuals' genetic profiles are now feasible, enhancing the effectiveness of interventions.

To promote longevity and lower biological age, pharmaceuticals, nutraceutical supplements, and other interventions should be considered as part of a comprehensive anti-ageing regimen that incorporates other complementary protocols. These may include adopting a healthful diet, engaging in regular exercise and resistance training, practising intermittent fasting, managing stress effectively, and optimising sleep patterns.