Comments on Rapamycin and Metformin

Three of the better known efforts to create a drug that modestly slows the rate of aging are centered on the following items:

Of these, ways to manipulate the activity of sirtuins have received the greatest attention over the past decade, but there is little to show for all that money and time beyond a modest gain in the understanding of metabolism. There are no replicated, solid results of life extension in mice via sirtuin-influencing drugs, and I'd go so far as to say that the field is under something of a cloud at present. Metformin is in a similar position: while a large body of work relates to its use as a treatment for type 2 diabetes, the evidence for its ability to extend life in laboratory animals is mixed at best. Rapamycin is the only one of the three that can boast solid, replicated evidence of life extension in mice. It is a drug that has been in use as an immunosuppressant for more than a decade, but its ability to extend life is a more recent finding.

For today I thought I'd point out a couple of open access items containing recent findings on the use of rapamycin and metformin in the context of aging. While I don't believe that this branch of research is particularly relevant to extending human life by any meaningful amount in the near term, it is interesting to watch and may help to shed more light on the relative importance of various aspects of our biology in aging. The metformin paper in particular is an educational attempt to tie in the senescent cell aspect of aging to study results:

Metformin, aging and cancer

Metformin, a widely used antidiabetic drug, has been linked to a reduced cancer incidence in some retrospective, hypothesis-generating studies. What is the mechanism by which aging may increase cancer incidence? Although many molecular changes correlate with aging, the presence of senescent cells capable of secreting inflammatory cytokines may be involved. This senescence associated secretory phenotype (SASP) consists of multiple cytokines, chemokines, growth factors and extracellular matrix degrading enzymes that can potentially affect normal tissue structure.

The SASP probably evolved as a gene expression program to assist the senescent tumor suppression response and tissue repair after damage and should be viewed as an initial adaptive response. However, [chronic] SASP [like chronic inflammation] may cause a microenvironment in old tissues that facilitates tumor initiation and then stimulates cancer cell growth.

This unfortunate interaction between senescent cells and cancer cells has been reproduced in experimental mouse models where senescent fibroblasts stimulated tumor progression. [During] experiments to study the potential cancer prevention activity of metformin, we found serendipitously that the drug prevented the expression of many proteases, cytokines and chemokines in senescent cells. We thus propose that metformin prevents cancer by modulating the SASP in tissues where senescent cells were not naturally cleared.

Prolonged Rapamycin treatment led to beneficial metabolic switch

In the first robust demonstration of pharmacologically-induced life extension in a mammal, rapamycin increased longevity of mice via either feeding or injection. However, rapamycin treatment also showed the detrimental metabolic effects, including hyperinsulinemia, hyperlipidemia, glucose intolerance and insulin resistance. Those observations present a paradox of improved survival despite metabolic impairments. How rapamycin extended lifespan with such paradoxical metabolic effects remains to be elucidated.

In the various studies of rapamycin treatment, length of rapamycin treatment varied from two weeks to two years. With short-term rapamycin treatment, mice showed the detrimental metabolic effects, while a much longer length (up to 1.5 to 2 years) of rapamycin treatment led to increased longevity. Duration of rapamycin treatment may be one of the key factors that determine outcomes of the treatment. Longer-term rapamycin treatment may cause beneficial metabolic "switch" that is associated with enhanced insulin signaling and extended longevity.

We [recently] reported that duration of rapamycin treatment indeed has differential effects on metabolism. In our study, rapamycin was given to mice for two, six or 20 weeks. Consistently with the previous reports, mice with two weeks of rapamycin treatment had characteristics of metabolic syndrome. Mice with six weeks of rapamycin treatment were in the metabolic transition status. When rapamycin treatment continued for 20 weeks, the detrimental metabolic effects were reversed or diminished.

It's worth taking some time to look over the state of research for these front-runners in the old-school drug discovery approach to extending life. I find it serves well as a way to inoculate yourself against unfounded optimism and unreasonable expectations, both now and the next time that both the "anti-aging" marketplace and biotech startups tout something that you can buy to supposedly influence metabolism and aging. If you have an enthusiasm for living longer, better to channel it into exercise, calorie restriction, and fundraising for the SENS Research Foundation.

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