Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice

Abstract

Making provocative headlines, three outstanding publications demonstrated that early-life treatment with rapamycin, including treatments during developmental growth, extends lifespan in animals, confirming predictions of hyperfunction theory, which views aging as a quasi-program (an unintended continuation of developmental growth) driven in part by mTOR. Despite their high theoretical importance, clinical applications of two of these studies in mice, Drosophila and Daphnia cannot be implemented in humans because that would require growth retardation started at birth. A third study demonstrated that a transient (around 20% of total lifespan in Drosophila) treatment with rapamycin early in Drosophila adult life is as effective as lifelong treatment, whereas a late-life treatment is not effective. However, previous studies in mice demonstrated that a transient late-life treatment is highly effective. Based on hyperfunction theory, this article attempts to reconcile conflicting results and suggests the optimal treatment strategy to extend human lifespan.

Keywords: geroscience; gerostatics; healthspan; senescence; sirolimus.

Figure 1

Critical time window for reprograming of aging by inhibiting developmental growth. (A) Treatment with rapamycin immediately after birth extended lifespan of normal mice. (B) Treatment with GH immediately after birth shortened lifespan of GH-deficient mice. GH-deficient mice have low activity of mTORC1. A and B are mirror images showing the same phenomenon.

Figure 2

Timing of rapamycin treatment in some animal studies. (A) Inhibition of growth during development. (B) Treatment in the earliest post-development. (C) Late-life treatment. Green: growth; Yellow: pre-diseases; Red: age-related diseases.

Figure 3

Hypothetical rapamycin treatment in humans for maximal longevity. Started early in post-development (for example, at 21 yo), low doses of rapamycin decelerate progression of pre-diseases (slow aging). Side effects are more undesirable at younger ages and doses should be low. Doses are gradually increased, to avoid rapamycin adaptation and to maximize therapeutic potential.