Can low IGF-1, DHEA-S, and testosterone reduce anabolic repair signaling in aging men?

Age-related declines in circulating testosterone, insulin-like growth factor 1 (IGF-1), and dehydroepiandrosterone sulfate (DHEA-S) directly compromise the cellular machinery responsible for tissue repair and energy production in aging men.

Downstream anabolic signaling

• Blunted signaling pathways: Testosterone and IGF-1 serve as primary activators of the intracellular phosphoinositide 3-kinase (PI3K)/Akt and mechanistic target of rapamycin (mTOR/mTORC1) pathways. Age-related hypogonadism and somatopause blunt this node, inducing anabolic resistance—a state where aged skeletal muscle fails to initiate protein synthesis or hypertrophy in response to physiological stimuli.
• Catabolic shift: Although DHEA-S acts primarily as an indirect steroid precursor, a clinically elevated cortisol-to-DHEA-S ratio drives muscle proteolysis and systemic catabolism.

Mitochondrial maintenance and tissue resilience

• Impaired biogenesis and mitophagy: Active IGF-1/Akt/mTOR and testosterone signaling upregulates peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1α) and YY1. This pathway coordinates mitochondrial biogenesis, ATP production, and BNIP3-mediated mitophagy.
• Loss of tissue integrity: Insufficient hormone availability downregulates PGC-1α, which arrests mitochondrial quality control and turnover. Combined with blunted satellite cell function, this mitochondrial decay directly accelerates sarcopenia and reduces general tissue resilience.

Bottom line

• Key takeaway: Sustained deficiencies in testosterone and IGF-1 blunt downstream Akt/mTOR/PGC-1α signaling. This molecular block impairs mitochondrial biogenesis and protein synthesis, directly driving sarcopenia and physical frailty in aging men.