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Present Calorie Restriction Mimetics are a Poor Substitute for the Practice of Calorie Restriction


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Posted 24 November 2021 - 08:11 PM


The portion of the medical research and development community that is focused on aging spends most of its time and funding on classes of treatment that cannot outperform good lifestyle choices when it comes to improving health and slowing degenerative aging. Why is this? If billions and decades are to be expended on building a pipeline from fundamental research through to clinical trials, why is the goal only an incremental benefit to health, smaller than that produced by regular exercise, intermittent fasting, or the practice of calorie restriction? Why such a lack of ambition, given the many possible projects that could achieve far more?

The small patient advocacy community focused on the treatment of aging as a medical condition spent long years convincing scientific and industry groups that it is both possible and desirable to extend the healthy human life span. The result of that work is, it appears, largely the initiation of projects that simply don't matter in the bigger picture, that won't meaningfully change the shape of later life, that won't greatly extend healthy human life spans.

Today's research materials are a reminder that the lion's share of effort and investment in the longevity industry is devoted to treatments and potential treatments that upregulate cellular stress responses, such as autophagy, to recreate a thin fraction of the natural metabolic outcomes of exercise, fasting, hypoxia, or calorie restriction. It remains the case that far too little attention is given to work that can in principle produce rejuvenation, by repairing the molecular damage that is the underlying cause of aging. Yes, senolytic therapies to clear senescent cells have made the leap, but senolytics see a fraction of the interest given to calorie restriction mimetics.

This is an important topic for continued patient advocacy. It is clearly not enough to convince the institutions of the world to work towards the treatment of aging; that is an important and ongoing battle, but it is only a first step. We must also advocate for a focus on the right sort of research programs, those that are in principle capable of producing sizable gains in health and life span, versus those that are not. If another two decades slip away with nothing to show for it but the clinical approval of varieties of mTOR inhibitor and other calorie restriction mimetic small molecule drugs, then a great opportunity to improve the human condition and save countless lives will have been squandered.

Diet trumps drugs for anti ageing and good metabolic health

A study comparing the impact of diet versus drugs on the inner workings of our cells has found nutrition has a much stronger impact. The pre-clinical study suggests the makeup of our diet could be more powerful than drugs in keeping conditions like diabetes, stroke, and heart disease at bay. Conducted in mice, the research showed nutrition (including overall calories and macronutrient balance) had a greater impact on ageing and metabolic health than three drugs commonly used to treat diabetes and slow down ageing: metformin, resveratrol, and rapamycin.

The research builds on the team's pioneering work in mice and humans demonstrating the protective role of diet and specific combinations of proteins, fats, and carbohydrates against ageing, obesity, heart disease, immune dysfunction, and risk of metabolic diseases, such as type 2 diabetes. Drugs can also target the same biochemical pathways as nutrients. There has been a huge effort to discover drugs aimed at improving metabolic health and ageing without requiring a change in diet. "We discovered dietary composition had a far more powerful effect than drugs, which largely dampened responses to diet rather than reshaped them."

Nutritional reprogramming of mouse liver proteome is dampened by metformin, resveratrol, and rapamycin

Nutrient sensing pathways influence metabolic health and aging, offering the possibility that diet might be used therapeutically, alone or with drugs targeting these pathways. We used the Geometric Framework for Nutrition to study interactive and comparative effects of diet and drugs on the hepatic proteome in mice across 40 dietary treatments differing in macronutrient ratios, energy density, and drug treatment (metformin, rapamycin, resveratrol). There was a strong negative correlation between dietary energy and the spliceosome and a strong positive correlation between dietary protein and mitochondria, generating oxidative stress at high protein intake. Metformin, rapamycin, and resveratrol had lesser effects than and dampened responses to diet. Rapamycin and metformin reduced mitochondrial responses to dietary protein while the effects of carbohydrates and fat were downregulated by resveratrol. Dietary composition has a powerful impact on the hepatic proteome, not just on metabolic pathways but fundamental processes such as mitochondrial function and RNA splicing.


View the full article at FightAging




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