The Safe, Largely Ineffective End of Biogerontology

The safe approach to develop treatments for aging is to find natural compounds and existing small molecule drugs with known safety profiles that can adjust metabolism to modestly slow aging. It doesn't aggravate those people with a conservative mindset who fear all change, even beneficial change. It is likely to be successful enough during clinical development to attract funding and give early investors a return on their investment. It is only an incremental step beyond present drug development processes, nothing radical that is likely to raise eyebrows. Thus much of the present longevity industry follows the incentives and takes the easier route.

Unfortunately, near everything derived from this philosophy of development will do very little for human life span. This end of the longevity industry will become just another arm of medical research and development that produces marginal therapies, most of which will fail in later clinical trials because the effect sizes are too small. Why is this the case? It is because researchers screen and test potential treatments in lower species, from yeast to nematode worms to mice, all of which have a much greater plasticity of life span in response to interventions that mimic the response to calorie restriction than is the case for longer-lived species such as our own. Thus most discoveries made in any unbiased search will be compounds that mimic the response to calorie restriction.

This mimicking typically means an upregulation of cellular housekeeping mechanisms such as autophagy. There is plenty of human data to show that calorie restriction, and thus the full panoply of such increased cellular maintenance, is beneficial to health. Calorie restriction doesn't, however, greatly extend life span in long-lived species such as our own: it would have been well known thousands of years ago were this the case. We can't add decades to healthy longevity via stress response upregulation of this sort.

This said, the approach of screening for novel compounds can in principle produce varieties of rejuvenation therapy that result in large improvements in late life health - such as senolytic compounds that selectively kill senescent cells. The development of senolytic therapies is a big win, and will be profoundly influential on human health once the existing low cost senolytics obtain solid clinical trial data and have percolated into common use. But this isn't the median outcome, and a discovery process that is more directed than screening for slowing of aging in mice or nematode worms is needed if we are to live meaningfully longer than our grandparents.

Antiaging agents: safe interventions to slow aging and healthy life span extension

Over the last three decades, some interventions and many preclinical studies have been found to show slowing aging and increasing the healthy lifespan of organisms from yeast, flies, rodents to nonhuman primates. The interventions are classified into two groups: lifestyle modifications and pharmacological/genetic manipulations. Some genetic pathways have been characterized to have a specific role in controlling aging and lifespan. Thus, all genes in the pathways are potential antiaging targets. Currently, many antiaging compounds target the calorie-restriction mimetic, autophagy induction, and putative enhancement of cell regeneration, epigenetic modulation of gene activity such as inhibition of histone deacetylases and DNA methyltransferases, are under development. It appears evident that the exploration of new targets for these antiaging agents based on biogerontological research provides an incredible opportunity for the healthcare and pharmaceutical industries.

Performing clinical trials to study the anti-aging potential of conventional drugs is undoubtedly a very difficult task. This is because older patients often suffer from multiple diseases and receive multiple medications simultaneously. The presence of drug-drug interactions and identified comorbidities make the evaluation of such drugs difficult, especially to assess the full range of effects produced by these drugs, whether beneficial or harmful. The lack of reliable and detectable biomarkers to assess the effectiveness of anti-aging interventions is another serious challenge.

The criteria for a potential anti-aging drug are: (1) a drug that extends the lifespan of a model organism, preferably a mammal; (2) a drug that delays or prevents some aging-related diseases in mammals; and (3) a drug that inhibits the senescence transition of cells from quiescence to senescence. The criteria may overlap. If an intervention is intended to extend lifespan, it must retard diseases associated with aging.

Many plants and fungi contain natural anti-aging products that can extend the lifespan of model organisms. These active molecules regulate the same cellular and physiological pathways that are affected by calorie restriction (CR) and exercise. Compounds that increase lifespan and healthspan mimic the effects of CR, typically by reducing insulin/IGF-1 signaling and activating autophagy and other cellular processes that increase resistance to stress.

Various strategies exist for using the anti-aging agents described here, including dietary supplements, increasing the intake of foods containing large amounts of these molecules, and/or consuming probiotics and prebiotics that raise blood levels of these molecules. Several nutrients and natural compounds have been observed to be related to increased lifespan in humans, suggesting that such strategies are feasible for slowing aging and increasing health span. Plant and fungal molecules with anti-aging properties in model organisms may also lead to the discovery and identification of new bioactive compounds for the development of improved CR mimetics to slow human aging. Except for mentioned above natural products, many other compounds have been reported to show anti-aging activity, such as acetic acid, allicin, apigenin, aspalathin, berberine, capsaicin, catalpol, celastrol, garcinol, huperzine, hydroxycitrate, inositol, naringin, piceatannol, and piperlongumine.

Biogerontology is entering a period of exciting and rapid development. It has great potential for future pharmacological interventions to slow aging. As a new era of anti-aging drug discovery dawns, the research community will need to pay special attention to the timely development of drugs that can slow the aging process, either alone or as multiple agents. Natural products provide the driving force to move forward in our quest to understand and improve the health span, just as they have always done! In regulating aging, it is hoped that these drugs will also reduce the burden of many age-related diseases.


I would add that if it doesn't extend the maximum human lifespan or if it doesn't take an average individual beyond what they can achieve with healthy living, it isn't really life extension. Life extension and rejuvenation research should be about breaking the barriers, not about achieving the barriers that we have had in place for thousands of years.

If we include all these treatments that only help us achieve the barriers, we would have to include everything that might extend our normal life, like wearing a seatbelt, not rock climbing without safety gear, not smoking, eating vegetables etc. All are great and important, but don't fit into this rejuvenation field. We should only include research as part of this field if it extends the maximum lifespan and improves our health beyond what is possible with healthy living.

I agree: Research and advocacy in this field needs to set its sights higher.

Posted by: Neil at May 21st, 2022 1:01 PM

I think this is really a case of the old adage, "if all you have is a hammer, every problem looks like a nail". Most of the research budget comes from pharmaceutical companies, and their thing of course, is small molecule drugs. So, naturally they attempt to solve every problem with small molecule drugs, even when it's clear that those problems require more sophisticated technologies to solve. They just throw the stuff they're familiar with at the problem, rather than work on developing new technologies.

Oh, and bear in mind the profit motive also; they're only incentivised to develop things that are merely good enough to sell; so basically, anything that does more than nothing, is "good enough". They're not incentivised much to develop new technologies to actually fix things, when they're doing "just fine" with what they have.

Posted by: Arcanyn at May 22nd, 2022 1:36 AM
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