Age-Related Gene Expression Signature in Rats Demonstrate Early, Late, and Linear Transcriptional Changes from Multiple Tissues.

To understand the changes in gene expression that occur as a result of age, which might create a permissive or causal environment for age-related diseases, we produce a multi-time point age-related gene expression signature (AGES) from liver, kidney, skeletal muscle, and hippocampus of rats, comparing 6-, 9-, 12-, 18-, 21-, 24-, and 27-month-old animals. We focus on genes that changed in one direction throughout the lifespan of the animal, either early in life (early logistic changes), at mid-age (mid-logistic), late in life (late-logistic), or linearly, throughout the lifespan of the animal. The pathways perturbed because of chronological age demonstrate organ-specific and more-global effects of aging and point to mechanisms that could potentially be counter-regulated pharmacologically to treat age-associated diseases. A small number of genes are regulated by aging in the same manner in every tissue, suggesting they may be more-universal markers of aging.

Partial Inhibition of mTORC1 in Aged Rats Counteracts the Decline in Muscle Mass and Reverses Molecular Signaling Associated with Sarcopenia.

There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, partial inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross-sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated and gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a "rapalog" (a pharmacological agent related to rapamycin). Therefore, partial mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.