Rapamycin in Early Life Delays Development and Modestly Extends Life Span in Mice

As a general rule, 10% life extension in mice via metabolic alteration is uninteresting. It depends on the fine details, of course, but most age-slowing interventions so far discovered are in some way upregulating cellular stress response mechanisms, or adjusting growth hormone signaling. Neither of these approaches works anywhere near as well in long-lived mammals, such as our own species, as it does in short-lived mammals, such as mice, and in lower animal species. Short-lived species have life spans that are very plastic in response to environmental cues, such as the lack of nutrients that provoke greater stress response activity. Calorie restriction can extend life in mice by as much as 40%, but certainly doesn't have that great an effect in humans. Growth hormone receptor knockout can extend mouse life span to an even greater degree, but humans with the analogous Laron syndrome don't appear to live significantly longer than the rest of us.

Today's open access paper reports on another novel dead end in considering the effects of metabolic change on longevity. Here, an mTOR inhibitor is given to mice in early life. The result is slowed development, reduced growth, and a modest 11.8% extension of median life span. mTOR inhibition is a well-proven way to modestly and reliably slow aging when used in later life in mice, but here the effects appear an amalgam of the usual mechanisms of stress response upregulation coupled with the reduced growth seen in mice in which growth hormone signaling is disabled. It is scientifically interesting to see that developmental effects can lead to this outcome, but the relevance to human medicine seems tenuous. At the end of the day, this is simply not an area of study that can plausibly lead to sizable gains in human healthy longevity.

Rapamycin treatment during development extends life span and health span of male mice and Daphnia magna

Some indirect evidence supports the causal relationship between inhibition of growth signaling and longevity if targeted during development. For example, growth hormone (GH) knockout mice and mice lacking GH production live up to 50% longer than their wild-type siblings. However, their longevity was diminished if they were treated with growth hormone during early postnatal development. At the same time, growth hormone knockout induced at adult age had limited to no effects on longevity. However, there have been no experiments where growth pathways are directly inhibited only during development and the longevity outcomes measured.

Rapamycin is a well-characterized mechanistic target of rapamycin (mTOR) inhibitor and is among the most validated and potent pharmaceutical interventions that extend life span in mice. Rapamycin can extend life span if given in adulthood or later in life in various mouse strains, including genetically diverse UMHET3 mice (a cross of four inbred strains). Rapamycin failed to extend the life span of growth hormone receptor knockout mice. Furthermore, early life (EL) rapamycin treatment was previously shown to suppress growth of mice. Thus, rapamycin is a perfect candidate to test how targeting growth only early in life can affect life span, and we used it in our study, examining its effects on longevity, health span, biological age, and gene expression.

Here, we subjected genetically diverse UMHET3 mice to rapamycin for the first 45 days of life. The mice grew slower and remained smaller than controls for their entire lives. Their reproductive age was delayed without affecting offspring numbers. The treatment was sufficient to extend the median life span by 10%, with the strongest effect in males, and helped to preserve health as measured by frailty index scores, gait speed, and glucose tolerance and insulin tolerance tests. Mechanistically, the liver transcriptome and epigenome of treated mice were younger at the completion of treatment. Analogous to mice, rapamycin exposure during development robustly extended the life span of Daphnia magna and reduced its body size. Overall, the results demonstrate that short-term rapamycin treatment during development is a novel longevity intervention that acts by slowing down development and aging, suggesting that aging may be targeted already early in life.


An interesting finding that may lead to a controversial public conundrum: if the most successful anti-ageing interventions occur pre-natally and restrict growth and development (e.g. average 4' - 5' humans not reaching reproductive maturity until late-20s or later, but then have an average life span well over 120, as an example, without any supporting evidence), does society tolerate such therapies? Does the longevity industry, with that kind of stigma or controversy, continue to research along that path? The longevity industry has not likely had to significantly deal with such possible sacrifices/ compromises/ political dramas. Such an industry may be better served in improving life, all else being as it is, over a longer period of reduced certainty and acceptance than risk such a schism.

Posted by: Jer at October 2nd, 2022 10:41 AM

I'm still not clear on Human Growth Hormone. In my early 40's, without going into the details, injectable HGH helped me get into the best shape I've ever been in, able to sustain a >150 BPM exercise routine, peaking at 175, for over 30 minutes, and burning 1,200 calories over an intense hour. I lost a bunch of fat during that ~7 months also. I'd do it again if the cancer risk wasn't there and it was both cheaper and more legal.

We need a serious study at various levels, at various ages, and various amounts of exercise and diet. I miss the energy and power those shots use to give me.

Posted by: Tom Schaefer at October 6th, 2022 3:08 PM
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