Metformin and sex: why suppression of aging may be harmful to young male mice

Anisimov et al. reported that lifelong treatment with metformin (an anti-diabetic drug with potentially anti-aging effects) was beneficial for female mice but shortened lifespan in males. Here I discuss why suppression of aging may be unfavorable in young males. Metformin is used for treatment of type II (adult-onset) diabetes. Also, metformin and its analog phenformin prevent cancer and increase lifespan in rodents [1-7]. Yet, effects of metformin depend on mice strains and gender. In one strain (transgenic female HER-2/neu mice), metformin slowed down aging and tumor development [3]. In another strain (female SHR mice), met-formin slowed down aging without inhibiting spontaneous tumorigenesis [4]. In third strain (female 129/Sv mice), metformin decreased carcinogenesis but only marginally increased life span [8]. Unexpectedly, in male mice of the same 129/Sv strain, metformin decreased the mean life span by 13% [8]. How can this be explained? There are 3 additional pieces to the puzzle. First, metformin via several mechanisms inhibits the mTOR pathway [9-15]. Second, inhibition of mTOR may explain the anti-aging effect of metformin [16,17]. Third, death rate was increased specifically in young males, thus decreasing their mean life span. Still, met-formin did not affect lifespan of the last 10% of survivors and maximum life span [8]. Death from " anti-aging " Growth and aging share a common molecular mechanism [18]. Preview and testosterone stimulate cellular growth in part by activating the mTOR pathway [19-30]. When a cell cannot grow in size, then activated mTOR contributes to senescent phenotype [31-33]. By promoting cellular aging, mTOR is involved in organismal aging and age-related diseases [34]. mTOR is essential earlier in life but also accelerates aging and age-related diseases (cancer). (Note: This is a clear-cut example of antagonistic pleiotropy [35]. As a matter of fact, any genetic pathway that accelerates aging must be beneficial earlier in life, otherwise it would be eliminated by, whatever weak, natural selection). Accelerated aging can be linked to vigor earlier in life [36,37]. In agreement, size and weight is associated with faster aging [38]. However, the degree of early-life benefits is slightly different in males and females. In the wild, young males have a higher risk of death (from accidents, competition and violence) than young females. (This is still the case in modern men and women). The higher death rate earlier in life, the more important is robustness. So males need to be stronger and bigger, to fight and compete …