Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration

Abstract

Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.

Senolytics improve muscle adaptation in old mice

“…β-Gal+ cells appear to transition to senescence in muscle from old mice, developing a senescence-associated secretory phenotype (SASP) relative to cells isolated from young mice 14 days post injury [ 1 ]. Some of these findings were recently confirmed by the Muñoz-Cánoves lab [ 5 ], who show a greater abundance of senescent cells early in the regenerative process that is reduced over time and greater in old versus young mice. They also show a reduction in senescent cell abundance in response to D+Q treatment following injury, associated with improved regeneration and improvements in muscle force production.…”

“…They also show a reduction in senescent cell abundance in response to D+Q treatment following injury, associated with improved regeneration and improvements in muscle force production. Using a senescent cell isolation approach comparable to ours, they also performed a comprehensive characterization of the SASP during muscle aging and regeneration [ 5 ]. They confirm that most senescent cells in muscle are likely derived from myeloid cells, but they also detected smaller satellite cell and fibroadipogenic cell populations that may contribute to the senescent phenotype.…”

“…They confirm that most senescent cells in muscle are likely derived from myeloid cells, but they also detected smaller satellite cell and fibroadipogenic cell populations that may contribute to the senescent phenotype. lt is important to note that our work shows young mice treated with D+Q display an attenuated regenerative response [ 1 ], whereas the Muñoz-Cánoves lab shows an improvement in the regenerative response of young mice as early as 7 days post injury [ 5 ]. Considering senescence has been shown to be required for the full regenerative response in skeletal muscle [ 4 ], the large overlap in phenotype between β-Gal+ macrophages and bona fide senescent cells likely contributes to the confusion and warrants further investigation.…”

Rejuvenation strategies share gene expression programs of reduced inflammation and downstream restored fatty acid metabolism

“…This is line with diverse evidence suggesting that lipid metabolism is an important regulator of aging in nematodes, fruit flies, mice, and rats 21 . Moreover, several other studies conducting transcriptomic analysis have reported changes in these pathways in the context of aging 22 (reduced), cellular senescence 23,24 (enhanced), HP 25 (enhanced), and especially in the context of CR 18,26–28 (enhanced), where it is highly foreseeable. Recently, the senolytic agents dasatinib and quercetin were shown to have similar effects on both inflammation and metabolism in adipose tissue, using targeted assays 29 .…”

Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail

“…Whole body p21 overexpression resulted in increased cellular senescence and muscle atrophy [ 8 ], and aged humans have an increased percentage of gamma H2A histone family member X (γH2AX) positive satellite cells [ 30 ]. Further, depletion of SA-β-galactosidase-positive macrophages in aged mice improved muscle regeneration [ 31 ], and introducing senescent cells to young mice during muscle recovery following chemical injury creates an aged-like microenvironment and impairs regeneration [ 32 , 33 ]. Together, these data indicate that interstitial cells and the cellular environment that are important in muscle remodeling are influenced by senescence.…”