Many natural and synthetic compounds have been proposed to extend lifespan in model organisms, and thus act as potential anti-aging drugs in humans. Notably, however, most of these compounds failed to do this reproducibly when tested, exhibiting profoundly varying effects in different species, contexts, and sexes, and all of them still await human validation in clinical trials. Moreover, for most of these interventions, tolerability, safety, and adverse effects are unknown, in particular in long-term administration as would be required for anti-aging therapy. Finally, it is unclear whether the proposed molecular targets, pathways, and mechanisms are indeed dysregulated in human aging, and if sex-, tissue- and cell type-specific differences exist. Abbreviations: mTOR: mammalian target of rapamycin; RAA, renin-angiotensin–aldosterone; ROS, reactive oxygen species.


Based on these caveats, it is not surprising that many pharmacological and interventional approaches have failed to live up to initial reports and promises. See this cite for proof of idea.
Keshavarz, M., Xie, K., Schaaf, K., Bano, D., & Ehninger, D. (2022). Targeting the “hallmarks of aging” to slow aging and treat age-related disease: Fact or fiction? Molecular Psychiatry.

For example, for the polyphenolic compound resveratrol, there is strong evidence that it does not directly bind to the proposed target, sirtuin 1 (SIRT1); many of the effects are only observed in specific mouse strains at very high doses and are dependent on co-administration of a high-fat diet; and effects in human clinical trials were small or non-existent (Furrer & Handschin, 2020; Handschin, 2016). Accordingly, clinical development of resveratrol derivatives was stopped 5 years after the acquisition of Sirtris Pharmaceuticals by GlaxoSmithKline in 2008, despite the 720 million US$ price tag paid to David Sinclair and Lenny Guarente.

Currently, metformin and rapamycin belong to the most discussed drugs to be repurposed for anti-aging treatments (Blagosklonny, 2021; Campisi et al., 2019). Clinical trials are planned for these drugs to assess geroprotective and lifespan-enhancing properties. However, in addition to mixed outcomes on mortality in humans or animal models (metformin) (Blagosklonny, 2021; Mohammed et al., 2021), and the immunosuppressing properties at least at some concentrations (rapamycin), other potential adverse effects have been reported. Importantly, potential beneficial anti-aging effects would have to outweigh the restrictions imposed on the many benefits of physical activity and other lifestyle-based interventions. Metformin seems to consistently reduce the effects of endurance and resistance training in humans, similar to what has been reported previously for resveratrol.

 

Another supplement scam: rapamycin-induced inhibition of mTOR blunts muscle hypertrophy in different contexts of muscle unloading and reloading in animal models (Morley, 2016). Unfortunately, the metformin and rapamycin studies in model organisms did not include an exercise arm. Such effects thus could not be assessed and might be of limited relevance in sedentary animals. However, this outcome is of high significance in the human population and is inadequately modeled by caged mice (Booth & Laye, 2009). Other adverse effects of these and other drugs will also have to be identified and evaluated in the long-term treatment of humans, as indicated by the potential of mTOR inhibition to affect β-amyloid plaques and the development of Alzheimer's disease

 

Another misunderstood drug is linked to when to use it. Few centralized papers realize aspirin is best used at night because of the effects of the circadian cycle it operates on. This is why few papers have shown that is effective in aging.

Although often neglected as an anti-aging drug, aspirin is another example of a reproducible compound in longevity studies (Campisi et al., 2019), with controversial outcomes on all-cause mortality in healthy elderly (McNeil et al., 2018). Of note, the exact identity, pharmacokinetics, tissue distribution, target mechanism, and other crucial pharmacological parameters of many of the proposed anti-aging compounds are not clear. Similarly, dosing, timing, age of initiation of treatment, and other considerations will have to be elucidated (Nelson et al., 2017).

 

Calorie restriction is also devoid of good proof but you'd never know it in functional medicine circles. Failures, controversies, and question marks are, however, not limited to proposed pharmacological anti-aging interventions. Caloric restriction robustly extends lifespan in various laboratory models, albeit with decreasing relative payoff when moving from simple to more complex, higher organisms (Dakic et al., 2022; Sohal & Forster, 2014). Notably, in rodents, sex- and strain-specific effects of caloric restriction were reported, which, in some strains, even had a negative effect on lifespan. Thus, the genetic background, time of day of feeding, nutrient composition, age at initiation of caloric restriction, the extent of caloric restriction, and other parameters seem to affect the outcome in rodent, non-human primate, and human studies (Campisi et al., 2019; Dakic et al., 2022; Sohal & Forster, 2014)
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In humans, the epidemiological data clearly show an unhealthy baseline of ad libitum food intake in many societies, linked to inadequate physical activity. Furthermore, basal, non-exercise activated thermogenic (NEAT) and activity-linked energy expenditure exhibits high interindividual differences, and for any caloric restriction intervention, baseline values and the targeted restriction would have to be strictly personalized. Finally, an implementation might be hampered by psychological factors, and side effects, for example frailty or cognitive performance, might occur (Hofer et al., 2022).

 

Cellular reprogramming and epigenetic rejuvenation refer to a collection of approaches attempting to leverage recent insights into tissue differentiation and de-differentiation (de Lima Camillo & Quinlan, 2021). Even though promising results in model organisms have been reported, many limitations and potential adverse effects will have to be overcome before safe application in humans can be envisioned. For example, the choice of reprogramming factors, tissue delivery, and control of expression, potential tissue de-differentiation or development of cancers have to be considered, in particular in the time scale of human aging and treatment (de Lima Camillo & Quinlan, 2021). Moreover, many of the proposed anti-aging drugs, including metformin, resveratrol, and rapamycin, decrease reprogramming efficiency at the concentrations for which life-extending benefits have been reported, described as the age reversal–age extension (Arae) paradox in which one anti-aging treatment adversely affects another (de Lima Camillo & Quinlan, 2021). As a final example, the usage of senolytics, aiming at the selective destruction of senescent cells, will have to address the biological function of cell senescence in differentiation, regeneration, tissue function maintenance and remodeling, wound healing, prevention of tumorigenesis, and other processes (Rhinn et al., 2019; Ring et al., 2022).

 

Mitochondria are constantly undergoing changes in morphology & distribution within the cytoplasm, as fused (network forming) or fissioned (punctate) mitochondria. When there’s a problem w/ fission, circadian control is lost = aging

 

Webinar : Reversing Physical Aging with Dr Thierry Hertoghe
14,399 views
Jan 26, 2018

 

Observing Circadian Rhythm is #1 but it has limitations.
Does monitoring
and supplementing and managing

IGF-1 IGFBP-3
thyroid
homocysteine
and
Steroid Hormone Panel
helps in maintaining health of a person at rather healthful levels.

Not necessarily extending life but extending the healthy and more energetic part of life.

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