Aging Muscle Fails Through Broken Cell-to-Cell Communication, Review Finds

Skeletal muscle does not simply wear out with age the way a machine loses parts. According to a comprehensive review published in Aging Cell, the progressive loss of muscle mass, strength, and regenerative power that defines sarcopenia is better understood as the collapse of an elaborate communication network among many cell types that normally cooperate to repair tissue. The authors argue that aging transforms muscle from a regenerative niche, in which stem cells, stromal cells, immune cells, blood vessels, and nerves coordinate repair with remarkable precision, into a degenerative niche in which those same populations actively undermine one another.

For decades, muscle aging was attributed mainly to intrinsic defects within myofibers or to the exhaustion of muscle stem cells, known as MuSCs. The review, drawing on recent single-cell RNA sequencing, spatial transcriptomics, multimodal atlases, and lineage-tracing studies, contends that these explanations are incomplete. Instead, aging reshapes the entire cellular ecosystem: stem cells lose regenerative competence, fibro-adipogenic progenitors become locked into pro-fibrotic states, immune populations fail to resolve inflammation, vascular support declines, and neuromuscular junctions undergo incomplete reinnervation. No single defect explains the decline; rather, it is the desynchronization of the whole system that drives tissue deterioration.

The fate of muscle stem cells illustrates this population-level remodeling. In geriatric mice aged twenty months or older, a fraction of MuSCs loses the capacity for reversible quiescence and drifts into a pre-senescent state, impairing later activation, proliferation, and self-renewal. Time-resolved trajectory analyses show that aged stem cells broadly preserve the overall sequence of activation and differentiation, but their responses are delayed and progress with highly heterogeneous kinetics. Epigenetic instability contributes to this decline: age-associated depletion of S-adenosylmethionine, a critical methyl donor, weakens repressive histone methylation and heterochromatin architecture, promoting DNA damage and apoptosis. Restoring intracellular SAM levels in experiments re-established heterochromatin domains and mitigated age-related regenerative defects.

One of the most provocative concepts in the review is what the authors call cellular survivorship bias. In aged stem cells, elevated expression of the tumor suppressor NDRG1 strongly suppresses mTOR signaling, a principal pathway governing cellular activation and expansion. This appears to function as a cellular brake that prioritizes long-term survival under chronic inflammatory and oxidative stress at the expense of rapid tissue repair. Pharmacologically inhibiting NDRG1 temporarily restores youthful activation and accelerates early repair, but repeated injury cycles lead to severe cellular stress and depletion of the remaining stem cell pool. The surviving cells in aged muscle, in other words, are not optimized for regeneration but selected for persistence under hostile conditions.

Immune dynamics add a second layer of dysfunction. After injury, platelets release chemokines such as CXCL4 and CXCL5 that recruit neutrophils and monocytes, which are later superseded by macrophages clearing debris and supporting myogenesis. In aged muscle, this choreography falters. Inflammatory and senescence-related immune programs persist beyond the window of productive repair, and specific aged M2-like macrophage subsets sustain secretion of pro-fibrotic factors including TGF-beta and osteopontin, driving neighboring stromal cells to deposit excess collagen. Meanwhile, the local accumulation of regulatory T cells, which normally dampen inflammation and supply pro-resolving signals such as IL-10, is markedly reduced or delayed. The result is a temporal mismatch: stem cells need an anti-inflammatory environment to build new fibers, yet the aged niche remains saturated with early inflammatory signals.

Fibro-adipogenic progenitors, or FAPs, are central players in this degenerative relay. In young tissue they transiently expand after injury, secrete extracellular matrix components that support myogenic progenitors, and then either self-eliminate or return to quiescence. Aging destroys this plasticity. Single-cell and spatial analyses reveal that aged FAPs diverge into aberrant states marked by osteopontin, Sca1, Dpp4, or, in human atlases, CD90 expression, all associated with chronic inflammation and fibrosis. Crucially, not all FAPs fail; subpopulations with anti-inflammatory, pro-regenerative signatures persist. The pathology is therefore not wholesale corruption of the stromal compartment but a loss of temporal plasticity, the inability to exit fibrotic states once repair is complete, leading to fibro-adipose remodeling that progressively replaces muscle with scar and fat.

The communication breakdown between stem cells and stromal cells is particularly well documented. FAP-derived WISP1 activates AKT signaling in MuSCs to promote productive proliferation, while fibronectin in the niche regulates adhesion and polarity through integrin-FAK signaling. Both supports decline with age. At the same time, epigenetically perturbed aged stem cells secrete IL-6, osteopontin, and CCN2, factors that push adjacent FAPs toward excessive expansion and collagen production. Senescent stem cells thus act not as passive casualties but as active instigators, propagating their defects through paracrine signaling. Genetic knockdown of CCN2 in aged MuSCs improves regenerative outcomes and attenuates fibrosis, while forced overexpression compromises engraftment and stimulates fibroblast expansion.

Senescence amplifies the damage through additional channels. Senescent FAPs secrete CCL2 and osteopontin, which entrap macrophages in a pro-inflammatory state and sustain a self-reinforcing macrophage-FAP feedback loop. In progeroid and dystrophic mouse models, eliminating senescent cells with the senolytic compound fisetin restores the stem cell pool and regenerative efficacy. Stress-induced senescent myoblasts release extracellular vesicles carrying senescence-associated cargo that induces secondary senescence in endothelial cells, compromising the vasculature repair depends on. Another senescent-cell product, the lipid 15d-PGJ2, covalently modifies the HRas protein in healthy neighboring myoblasts, hyperactivating ERK signaling and blocking myogenic differentiation. These findings show that the senescence-associated secretory phenotype extends well beyond soluble cytokines to transferable, non-protein signals.

The neuromuscular junction constitutes a specialized microdomain where these failures converge. Synaptic destabilization and motor unit remodeling often precede measurable sarcopenia, producing a mosaic of denervated, reinnervated, and unstable myofibers. Terminal Schwann cells guide regenerating axons back to motor endplates, and their ablation in adult mice severely impairs reinnervation and force recovery. Mesenchymal progenitors near motor axons supply trophic support, most notably the protein BMP3B, whose expression declines with age in both mice and humans; sustained expression in aged mice attenuates neuromuscular degeneration, muscle atrophy, and functional decline. Intriguingly, osteopontin displays context-dependent duality: it drives chronic fibrosis in the broader stroma yet acts as an indispensable neurotrophic factor at the synapse, a caution against blunt therapeutic targeting.

The review closes with a sober assessment of what remains unknown. Most ligand-receptor interactions proposed by computational analyses of omic data are still correlative, and only a limited set of signaling pathways, including WISP1 supplementation, CD47 blockade, and senescent FAP clearance, have been functionally validated in vivo. A further challenge is the translational gap between acute, synchronized murine injury models and the chronic, insidious muscle attrition characteristic of human sarcopenia. The authors argue that effective rejuvenation strategies must abandon single-cell targets in favor of restoring the entire multicellular network: stem-stromal crosstalk, immune resolution, vascular support, and neuromuscular communication. Treating aging muscle as an interconnected system, they conclude, offers the most realistic path toward dismantling degenerative loops and preserving strength in old age.

Subject of Research: Multicellular crosstalk and population dynamics in skeletal muscle aging and sarcopenia

Article Title: From Regenerative to Degenerative Niche: Multicellular Crosstalk and Population Dynamics in Skeletal Muscle Aging

Article References: Kim, S., Kim, M. J., & Yang, Y. R. (2026). From Regenerative to Degenerative Niche: Multicellular Crosstalk and Population Dynamics in Skeletal Muscle Aging. Aging Cell, 25(10), Article e70733. https://doi.org/10.1111/acel.70733

Image Credits: AI Generated

DOI: 10.1111/acel.70733

Keywords: skeletal muscle aging, sarcopenia, muscle stem cells, fibro-adipogenic progenitors, single-cell RNA sequencing, spatial transcriptomics, cellular senescence, macrophages, fibrosis, neuromuscular junction, intercellular communication, regeneration