## 2 Mechanistic Foundations of Skeletal Muscle Aging
### Mechanisms of Muscle Aging and Regeneration Decline  
With aging, satellite cell function declines due to both intrinsic changes and an altered niche environment. Aged satellite cells (Figure 3) exhibit diminished proliferative and regenerative capacity, impaired mitochondrial dynamics, reduced autophagy, and increased expression of senescence markers such as p16 INK4a, p21, and SA-\(\beta\)-gal [10; 18; 37; 38; 42; 43; 44; 45; 46].  
Telomere shortening and epigenetic drift also contribute to impaired function and replicative exhaustion. Systemically, chronic low-grade inflammation, hormonal imbalance (e.g., reduced insulin-like growth factor 1 (IGF-1) and testosterone), and disrupted nutrient-sensing pathways (e.g., reduced NAD\({}^{+}\)/sirtuin11 (SIRT1) activity and increased mTOR1 hyperactivation) accelerate satellite cell aging [18; 38]. The aged ECM becomes stiffer, enriched in crosslinked collagen and fibronectin, and less conducive to regenerative signaling. Increased secretion of TGF-\(\beta\) and fibrogenic cytokines by fibro-adipogenic progenitors (FAPs) promotes fibrosis and impairs satellite cell activation [47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58]. Myofiber atrophy is driven by multiple converging factors: mitochondrial dysfunction leads to ATP depletion and excess reactive oxygen species (ROS) production, NAD\({}^{+}\) depletion reduces sirtuin activity and impairs mitochondrial quality control, and inflammaging maintains persistent activation of NF-kB, promoting proteolysis via the ubiquitin-proteasome and autophagy-lysosome systems. These disruptions alter signaling through mTOR, adenosine monophosphate-activated protein kinase (AMPK), and Forkhead box O (FoxO) signaling pathways, reducing protein synthesis, increasing degradation, and compromising stress resilience [18; 59; 60; 61; 62; 63; 64; 65; 66; 67; 68]. Progressive loss of neuromuscular junction (NMJ) integrity and reduced innervation further accelerate sarcopenia. Emerging markers of aging muscle include elevated levels of pro-inflammatory cytokines (e.g., IL-6 and TNF-\(\alpha\)), circulating senescence-associated secretory phenotype (SASP) factors, altered mitochondrial DNA  
Figure 3: Cellular consequences of aging in muscle stem cells. This schematic compares a young muscle stem cell with an aged stem cell, highlighting the intracellular hallmarks of aging. In youthful cells, mitochondria, protein folding, and autophagy pathways are intact, enabling effective energy production, repair, and proteostasis. With aging, stem cells accumulate protein aggregates, exhibit impaired autophagy, and suffer mitochondrial damage. These changes lead to oxidative stress (\(\uparrow\) Reactive Oxygen Species ROS), DNA damage, and reduced regenerative capacity. Dysfunctional lysosomes and endoplasmic reticulum contribute to further metabolic decline. Collectively, these disruptions impair satellite cell homeostasis, contributing to sarcopenia and diminished muscle repair.  
content, and increased oxidative damage markers such as 8-oxo-dG and lipid peroxidation products. These biomarkers can inform the early detection of regenerative decline and guide targeted interventions [18; 38; 62; 69; 70; 71; 72; 73; 74; 75; 76; 77; 78].