Anti-Aging with drugs hopes to achieve life extension to 120 years and beyond

Fighting aging has excellent coverage of antiaging research. They have pointed out a few recent overviews of the state and prospects of life extension using metabolic modification using drugs. Fighting aging and Aubrey de Grey (SENS) doubt that metabolic modification will yield significant life extension results. However there could be some life extension and health improvements and others like David Sinclair are more optimistic.

David Sinclair of Sirtris leads research on a few lines of calorie restriction mimetic drug development based on sirtuins.

David Sinclair believes we can expect to see people live to 120 and beyond within our lifetime. Harvard University’s Professor David Sinclair is working on a ‘cure for ageing’ and believes modern medicine can significantly extend the human lifespan. “I think there will be a world where people can look forward to living at least beyond 100, and it will be not uncommon where people can live to 120.

There are drugs already in clinical trials and, so far, they seem to be safe and showing early signs of success. “Instead of just lowering your cholesterol this pill would prevent Alzheimer’s disease, lung diseases, bowel diseases, dementia, a whole list of diseases… That’s what we’re able to do in mice so far. The question is: can we do that in people, and how soon?

Rapamycin is the leading longevity enhancing drug candidate

Fighting aging on Rapamycin. There is presently some debate over whether or not rapamycin actually slows aging – based on rigorous studies some researchers say yes, say no, it extends life in mice but only by reducing cancer risk. Rapamycin and various derivatives under development are presently the longevity enhancing drug candidates best supported by the evidence in laboratory mice, so there is probably a lesson to be learned here in regards to the soundness of the whole strategy of trying to slow aging via metabolic manipulation.

A case is made that Rapamycin does more than reduce cancer but increases longevity.

Cancer and aging

Cancer is an aging-related disease and interventions that slow aging (e.g. calorie restriction) delay cancer. Furthermore, compared with calorie restriction, rapamycin stronger inhibits MTOR. It is predictable that if rapamycin slows aging, it should delay cancer. Studies support these predictions and rapamycin extended lifespan and delayed cancer, even when calorie restriction did not. Although rapamycin is a potent cancer-preventive agent, it is only modestly effective for cancer treatment. Rapalogs are most effective in drug combinations. They also may decrease side effects by suppressing senescence of normal cells. Also, senescence of normal cells creates cancer-promoting micro-environment. If rapamycin indeed prevents cancer by slowing aging (not by killing cancer cells), the prevention must be started before cancer is initiated. In other words, if rapamycin treatment is started too late in life, then its anti-cancer effect will be blunted. This was shown in cancer-prone p53+/- mice. The same was shown by Neff et al: rapamycin rapamycin did not prevent cancer when the treatment was started at middle and old age. Thus, the JCI study confirms the notion that rapamycin delays cancer by slowing aging (see also discussion here in the last section). Anti-cancer effects simply cannot be responsible for life extension by rapamycin. First, effective anti-cancer drugs that are curative in lymphomas, testicular and ovarian cancers (methotrexate, cisplatin, paclitaxel) would greatly shorten murine lifespan, especially when started in young age. Even further, typical anti-cancer drugs accelerate cancer. For example, radiation (a classic anti-cancer intervention) dramatically accelerates cancer in p53+/- mice and shortens life span. And anti-cancer drugs cause secondary cancers in patients. In contrast, not only rapamycin extends lifespan, it is the only known drug that extends life span consistently. Second, apart from cancer-prone strains of mice, cancer is not the main cause of death in most animals. MTOR is involved in most age-related diseases and rapamycin prevents them in mammals and slows down aging. Finally, yeast, worm and flies do not die from cancer and still inhibition of the MTOR pathway extends lifespan.

Inhibition of TOR slows aging: converging evidence

1. Rapamycin suppresses geroconversion: conversion from cellular quiescence to senescence. Geroconversion is cellular basis of organismal aging.
2. Genetic manipulations that inhibit the TOR pathway extend life-span in diverse species from yeast to mammals
3. Rapamycin extends lifespan in all species tested
4. Calorie restriction, which inhibits MTOR, extends lifespan
5. MTOR is involved in diseases of aging and rapamycin prevents these diseases in animal models

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