Summary: Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age‐dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age‐dependent decline in spontaneous activity, occur more slowly in rapamycin‐treated mice, suggesting strongly that rapamycin retards multiple aspects of aging in mice, in addition to any beneficial effects it may have on neoplastic disease. We also note, however, that mice treated with rapamycin starting at 9 months of age have significantly higher incidence of testicular degeneration and cataracts; harmful effects of this kind will guide further studies on timing, dosage, and tissue‐specific actions of rapamycin relevant to the development of clinically useful inhibitors of TOR action.

1 Differences in the effect of age on structure-function relationships of limb muscles of mdx (dystrophin null) and control mice have not been resolved. We tested the hypotheses that, compared with limb muscles from age-matched control mice, limb muscles of 6- to 17-month-old mdx mice are larger but weaker, with lower normalised force and power, whereas those from 24- to 28-month-old mdx mice are smaller and weaker. 2 The maximum isometric tetanic force (P_o) and power output of limb muscles from 6-, 17-, 24- and 28-month-old mdx and control mice were measured in vitro at 25 °C and normalised with respect to cross-sectional area and muscle mass, respectively. 3 Body mass at 6 and 28 months was not signifcantly different in mdx and control mice, but that of control mice increased 16 % by 17 months and then declined 32 % by 28 months. The body masses of mdx mice declined linearly with age with a decrease of 25 % by 28 months. From 6 to 28 months of age, the range in the decline in the masses of EDL and soleus muscles of mdx and control mice was from 16 to 28 %. The muscle masses of mdx mice ranged from 9 % to 42 % greater than those of control mice at each of the four ages and, even at 28 months, the masses of EDL and soleus muscles of mdx mice were 17 % and 22 % greater than control values. 4 For mdx mice of all ages, muscle hypertrophy was highly effective in the maintenance of control values for absolute force for both EDL and soleus muscles and for absolute power of soleus muscles. Throughout their lifespan, muscles of mdx mice displayed significant weakness with values for specific P_o and normalised power ≈20 % lower than values for control mice at each age. For muscles of both strains, normalised force and power decreased ≈28 % with age, and consequently weakness was more severe in muscles of old mdx than in those of old control mice.

Oxidative stress has been implicated in the etiology of age‐related muscle loss (sarcopenia). However, the underlying mechanisms by which oxidative stress contributes to sarcopenia have not been thoroughly investigated. To directly examine the role of chronic oxidative stress in vivo , we used a mouse model that lacks the antioxidant enzyme CuZnSOD (Sodl). Sod1 ^−/− mice are characterized by high levels of oxidative damage and an acceleration of sarcopenia. In the present study, we demonstrate that muscle atrophy in Sod1 ^−/− mice is accompanied by a progressive decline in mitochondrial bioenergetic function and an elevation of mitochondrial generation of reactive oxygen species. In addition, Sod1 ^−/− muscle exhibits a more rapid induction of mitochondrial‐mediated apoptosis and loss of myonuclei. Furthermore, aged Sod1 ^−/− mice show a striking increase in muscle mitochondrial content near the neuromuscular junctions (NMJs). Despite the increase in content, the function of mitochondria is significantly impaired, with increased denervated NMJs and fragmentation of acetylcholine receptors. As a consequence, contractile force in aged Sod1 ^−/− muscles is greatly diminished. Collectively, we show that Sod1 ^−/− mice display characteristics of normal aging muscle in an accelerated manner and propose that the superoxide‐induced NMJ degeneration and mitochondrial dysfunction are potential mechanisms of sarcopenia.—Jang, Y. C., Lustgarten, M. S., Liu, Y., Muller, F. L., Bhattacharya, A., Liang, H., Salmon, A. B., Brooks, S. V., Larkin, L., Hayworth, C. R., Richardson, A., and Van Remmen, H. Increased superoxide in vivo accelerates age‐associated muscle atrophy through mitochondrial dysfunction and neuro‐muscular junction degeneration. FASEB J. 24, 1376–1390 (2010). www.fasebj.org