Aging is accompanied by a decline in physiological integrity and a loss of regenerative capacity in many tissues. The development of interventions that prevent or reverse age‐related disease requires ...a better understanding of the interplay of cell intrinsic, inter‐cellular communication and systemic deregulations that underlie the aging process. Immune dysfunction and changes in inflammatory pathways are transversal contributors to the aging process and are essential propagators of tissue deterioration. Here, we propose and discuss the rejuvenation potential of interventions that target chronic inflammation and how modulation of tissue repair capacity could be an important mediator of such anti‐aging strategies. We highlight how current knowledge on the systemic nature of inflammatory dysregulation in old organisms, together with the development of new animal models that allow for the isolation of the inflammatory component of aging, could provide new targets for interventions in aging based on the modulation of inflammatory pathways.
During aging, chronic inflammation and tissue damage create an auto amplifying loop driving tissue dysfunction and disease. Immune modulatory interventions that restore a regulated inflammatory response to support tissue repair could be envisioned as rejuvenating strategies to promote health and longevity.
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.
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.
Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this ...paper, we report new roles for MKP-1 (mitogen-activated protein kinase MAPK phosphatase-1) in controlling macrophage phenotypic transitions necessary for appropriate muscle stem cell-dependent tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to antiinflammatory macrophage transition and the later progression into a macrophage exhaustion-like state characterized by cytokine silencing, thereby permitting resolution of inflammation as tissue fully recovers. p38 hyperactivation in macrophages lacking MKP-1 induced the expression of microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin homologue) levels, thereby extending AKT activation. In the absence of MKP-1, p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene program and final cytokine silencing in macrophages, resulting in impaired tissue healing. Such defects were reversed by temporally controlled p38 inhibition. Conversely, miR-21-AKT interference altered homeostasis during tissue repair. This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, miR-21, and AKT activities may have implications in chronic inflammatory degenerative diseases.
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.
Regenerative therapies are limited by unfavorable environments in aging and diseased tissues. A promising strategy to improve success is to balance inflammatory and anti-inflammatory signals and ...enhance endogenous tissue repair mechanisms. Here, we identified a conserved immune modulatory mechanism that governs the interaction between damaged retinal cells and immune cells to promote tissue repair. In damaged retina of flies and mice, platelet-derived growth factor (PDGF)-like signaling induced mesencephalic astrocyte-derived neurotrophic factor (MANF) in innate immune cells. MANF promoted alternative activation of innate immune cells, enhanced neuroprotection and tissue repair, and improved the success of photoreceptor replacement therapies. Thus, immune modulation is required during tissue repair and regeneration. This approach may improve the efficacy of stem-cell-based regenerative therapies.
Src family kinases (SFKs) have long been implicated in tumorigenesis, but the exact requirement for individual kinase members, and their specific spatially and temporally defined roles in the ...maintenance of epithelial homeostasis remained unclear. A study by Cordero et al () now combines the strengths of Drosophila and mouse models for intestinal epithelial regeneration to characterize the role of individual SFKs in epithelial stem cells, tissue regeneration, and tumorigenesis.
The experimental power of Drosophila and mouse models enables the functional dissection of distinct Src family kinase family members in the homeostasis of intestinal stem cells.
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.
Regeneration is an important process in multicellular organisms, responsible for homeostatic renewal and repair of different organs after injury. Immune cell activation is observed at early stages of ...the regenerative response and its regulation is essential for regenerative success. Thus, immune regulators play central roles in optimizing regenerative responses. Neurotrophic factors (NTFs) are secreted molecules, defined by their ability to support neuronal cell types. However, emerging evidence suggests that they can also play important functions in the regulation of immune cell activation and tissue repair. Here we discuss the literature supporting a role of NTFs in the regulation of inflammation and regeneration. We will focus, in particular, in the emerging roles of mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) in the regulation of immune cell function and in the central role that immune modulation plays in their biological activity
. Finally, we will discuss the potential use of these factors to optimize regenerative success
, both within and beyond the nervous system.
Recent advances in our understanding of tissue regeneration and the development of efficient approaches to induce and differentiate pluripotent stem cells for cell replacement therapies promise ...exciting avenues for treating degenerative age-related diseases. However, clinical studies and insights from model organisms have identified major roadblocks that normal aging processes impose on tissue regeneration. These new insights suggest that specific targeting of environmental niche components, including growth factors, ECM, and immune cells, and intrinsic stem cell properties that are affected by aging will be critical for the development of new strategies to improve stem cell function and optimize tissue repair processes.
Neves et al. discuss the ways that aging impairs normal tissue regeneration and propose regenerative medicine strategies for treating age-related diseases and enhancing tissue repair by targeting both environmental and stem cell-intrinsic aging mechanisms.
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