Aging is characterized by the progressive dysfunction of most tissues and organs, which has been linked to the regenerative decline of their resident stem cells over time. Skeletal muscle provides a ...stark example of this decline. Its stem cells, also called satellite cells, sustain muscle regeneration throughout life, but at advanced age they fail for largely undefined reasons. Here, we discuss current understanding of the molecular processes regulating satellite cell maintenance throughout life and how age‐related failure of these processes contributes to muscle aging. We also highlight the emerging field of rejuvenating biology to restore features of youthfulness in satellite cells, with the ultimate goal of slowing down or reversing the age‐related decline in muscle regeneration.
Satellite cell rejuvenation requires combined interventions, involving rejuvenation of intrinsic properties of the satellite cell along with interventions that modulate the systemic and local environment to optimize the tissue repair response. These combinatorial interventions can be envisioned as a path for rejuvenation of skeletal muscle tissue function and regenerative capacity.
The contribution of cellular senescence to a diverse range of biological processes, including normal physiology, ageing, and pathology were long overlooked but have now taken centre stage. In this ...Editorial, we will briefly outline the review and original work articles contained in The FEBS Journal's Special Issue on Senescence in Ageing and Disease. It is beginning to be appreciated that senescent cells can exert both beneficial and adverse effects following tissue injury. Additionally, while these cells play critical roles for maintaining a healthy physiology, they also promote ageing and certain pathological conditions (including developmental disorders). Progress has been made in re‐defining and identifying senescent cells, especially in slow‐proliferating or terminally differentiated tissues, such as the brain and cardiovascular system. Novel approaches and techniques for isolating senescent cells will greatly increase our appreciation for senescent properties in tissues. The inter‐organ communication between senescent cells and other residents of the tissue microenvironment, via the senescence‐associated secretory phenotype (SASP), is a focus of several reviews in this Special Issue. The importance of the SASP in promoting tumour development and the evolution of SARS CoV‐2 variants is also highlighted. In one of the two original articles included in the issue, the impact of dietary macronutrients and the presence of senescent cells in mice is investigated. Lastly, we continue to deepen our understanding on the use of senolytics and senomorphics to specifically target senescent cells or their secreted components, respectively, which is discussed in several of the reviews included here.
In this Editorial, Darren Baker, Masashi Narita and Pura Muñoz‐Cánoves outline the content of The FEBS Journal's Special Issue on Senescence in Ageing and Disease. The issue features an exciting collection of articles that focus on the contribution of cellular senescence to a diverse range of biological processes, including novel physiology, ageing, and pathology. Importantly, the use of senolytics and senomorphics to specifically target senescent cells or their secreted components, respectively, is overviewed in several reviews of the issue.
Adult stem cells, particularly those resident in tissues with little turnover, are largely quiescent and only activate in response to regenerative demands, while embryonic stem cells continuously ...replicate, suggesting profoundly different regulatory mechanisms within distinct stem cell types. In recent years, evidence linking metabolism, mitochondrial dynamics, and protein homeostasis (proteostasis) as fundamental regulators of stem cell function has emerged. Here, we discuss new insights into how these networks control potency, self-renewal, differentiation, and aging of highly proliferative embryonic stem cells and quiescent adult stem cells, with a focus on hematopoietic and muscle stem cells and implications for anti-aging research.
García-Prat et al. discuss new insights into how metabolism, mitochondrial dynamics, and protein homeostasis (proteostasis) regulate embryonic and adult stem cell function and the implications for anti-aging research.
Skeletal muscle has a remarkable capacity to regenerate by virtue of its resident stem cells (satellite cells). This capacity declines with aging, although whether this is due to extrinsic changes in ...the environment and/or to cell-intrinsic mechanisms associated to aging has been a matter of intense debate. Furthermore, while some groups support that satellite cell aging is reversible by a youthful environment, others support cell-autonomous irreversible changes, even in the presence of youthful factors. Indeed, whereas the parabiosis paradigm has unveiled the environment as responsible for the satellite cell functional decline, satellite cell transplantation studies support cell-intrinsic deficits with aging. In this review, we try to shed light on the potential causes underlying these discrepancies. We propose that the experimental paradigm used to interrogate intrinsic and extrinsic regulation of stem cell function may be a part of the problem. The assays deployed are not equivalent and may overburden specific cellular regulatory processes and thus probe different aspects of satellite cell properties. Finally, distinct subsets of satellite cells may be under different modes of molecular control and mobilized preferentially in one paradigm than in the other. A better understanding of how satellite cells molecularly adapt during aging and their context-dependent deployment during injury and transplantation will lead to the development of efficacious compensating strategies that maintain stem cell fitness and tissue homeostasis throughout life.
A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to ...physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.
The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory ...cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.
Aging of an organism is associated with the functional decline of tissues and organs, as well as a sharp decline in the regenerative capacity of stem cells. A prevailing view holds that the aging ...rate of an individual depends on the ratio of tissue attrition to tissue regeneration. Therefore, manipulations that favor the balance towards regeneration may prevent or delay aging. Skeletal muscle is a specialized tissue composed of postmitotic myofibers that contract to generate force. Satellite cells are the adult stem cells responsible for skeletal muscle regeneration. Recent studies on the biology of skeletal muscle and satellite cells in aging have uncovered the critical impact of systemic and niche factors on stem cell functionality and demonstrated the capacity of aged satellite cells to rejuvenate and increase their regenerative potential when exposed to a youthful environment. Here we review the current literature on the coordinated relationship between cell extrinsic and intrinsic factors that regulate the function of satellite cells, and ultimately determine tissue homeostasis and repair during aging, and which encourage the search for new anti‐aging strategies.
Skeletal muscle relies on adult stem cells (satellite cells) to regenerate and this capacity declines with aging. Aged satellite cells improve their regenerative potential when exposed to a youthful environment. We review the literature on the coordinated relationship between extrinsic and intrinsic factors regulating satellite cells functions, which in turn determine tissue homeostasis and repair during aging.
Duchenne muscular dystrophy (DMD) is one of the most devastating neuromuscular genetic diseases caused by the absence of dystrophin. The continuous episodes of muscle degeneration and regeneration in ...dystrophic muscle are accompanied by chronic inflammation and fibrosis deposition, which exacerbate disease progression. Thus, in addition of investigating strategies to cure the primary defect by gene/cell therapeutic strategies, increasing efforts are being placed on identifying the causes of the substitution of muscle by non-functional fibrotic tissue in DMD, aiming to attenuate its severity. Congenital muscular dystrophies (CMDs) are early-onset diseases in which muscle fibrosis is also present. Here we review the emerging findings on the mechanisms that underlie fibrogenesis in muscular dystrophies, and potential anti-fibrotic treatments.
Autofluorescence (AF) is an intrinsic characteristic of cells caused by the presence of fluorescent biological compounds within the cell; these can include structural proteins (e.g., collagen and ...elastin), cellular organelles, and metabolites (e.g., aromatic amino acids). In flow cytometric studies, the presence of AF can lead to reduced antigen and population resolution, as well as the presence of artifacts due to false positive events. Here, we describe a methodology that uses the inherent ability of full spectrum cytometry to treat AF as a fluorochrome and to thereby separate it from the other fluorochromes of the assay. This method can be applied to complex inflamed tissues; for instance, in regenerating skeletal muscle we have developed a 16‐color panel targeting highly autofluorescent myeloid cells. This represents a first step toward overcoming technological limitations in flow cytometry due to AF.
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent ...stem-cell states distinguished by relative CD34 expression: CD34
, with stemness properties (genuine state), and CD34
, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.
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