Fight Aging!

Many of the readers here will be familiar with the very long-running studies of calorie restriction in rhesus macaques. There was some discussion of the data a few years ago. The research has continued since then, and here researchers report on their investigation of the biochemistry of calorie restriction in connection to the slowed aging of muscle tissue observed in these animals. Calorie restriction produces sweeping changes in the operation of cellular metabolism, and aging is itself a very complex process, even though it stems from simpler root causes. Research into the tissue-specific details of how and why calorie restriction slows specific aspects of aging is thus a slow and complex undertaking.

Our studies of aging in rhesus monkey and calorie restriction (CR) include a comprehensive investigation of age-related change including physical parameters. Similar to humans, muscle mass loss begins in middle age in monkeys at ∼15 years of age, where age-related loss of quadricep bulk from ∼15 to +25 years of age is ∼23% for females and 27% for males. Vastus lateralis (VL) is one of the four constituent muscle groups within the quadriceps, and it is the one that is the most vulnerable to aging, with 40% lower tissue weight for old monkeys (∼30 years of age) at necropsy compared with young adults of full stature (∼8 years of age). VL comprises both oxidative and glycolytic fiber types and succumbs to fiber atrophy and increased fibrosis with age in humans and monkeys. Responses to aging are of a fiber-type-specific nature: slow twitch type I fibers are resistant to age-related atrophy, but fast twitch type II fibers exhibit a gradual decline in cross-sectional area beginning at middle age.

Defects in skeletal muscle energy metabolism with age have been documented in humans, rats, and mice. In humans, skeletal muscle mitochondrial activity declines with age. In rhesus monkeys, age-related changes in mitochondrial and redox metabolism occur in advance of the onset of muscle mass loss and before age-related declines in physical activity are detected, suggesting that metabolism could play a causal role in skeletal muscle aging. A separate study has demonstrated that energy metabolism pathways are uniformly but modestly induced with CR in mice, and pathway level analysis confirmed the same in rhesus monkey skeletal muscle.

To test this, we investigated the molecular and cellular phenotypes of delayed sarcopenia due to CR in rhesus monkeys and related these data to tissue, biometric, and functional outcomes. We show that CR induced profound changes in muscle composition and the cellular metabolic environment. Bioinformatic analysis linked these adaptations to proteostasis, RNA processing, and lipid synthetic pathways. At the tissue level, CR maintained contractile content and attenuated age-related metabolic shifts among individual fiber types with higher mitochondrial activity, altered redox metabolism, and smaller lipid droplet size. Biometric and metabolic rate data confirm preserved metabolic efficiency in CR animals that correlated with the attenuation of age-related muscle mass and physical activity. These data suggest that CR-induced reprogramming of metabolism plays a role in delayed aging of skeletal muscle in rhesus monkeys.

Link: https://doi.org/10.1016/j.cels.2019.12.002