One step closer to finding the Fountain of Youth in our muscles: can we grow old while staying young at heart?

Commentary on ‘Aging disrupts muscle stem cell function by impairing matricellular WISP1 secretion from fibro-adipogenic progenitors’ by L. Lukjanenko et al., Cell Stem cell, 2019.¹

Senectus ipsa morbus est [Publius Terentius Afer: Phormio: a. IV, (160 B.C.)]: ageing is itself a disease. The quest of eternal youth has always been a major dream for humanity, from mythology up to current science. People worldwide are living longer with the population over 60 years old raising up to 2 billion by 2050.² Thus, the pursuit for a molecular ‘holy grail’ for ageing, if not healthy, at least smarter, is a medical demand.

The decline of working potential and regenerative properties is main hallmarks of tissue aging. The skeletal muscle healing restorative capacity relies on activation of resident progenitors, the muscle stem cells (MuSCs), which become less responsive and dysregulated as getting elderly.³ Recently, Lukjanenko et al.¹ elegantly addressed ageing detrimental influence on MuSCs in mice. Authors focused on the functional paracrine cross-talk between MuSCs and their regulatory cells in the skeletal muscle niche, namely fibro-adipogenic precursors (FAPs). Ageing significantly affects FAPs, as they fail to support MuSC renewal and differentiation and increase their pro-fibrotic commitment after muscle injury. On the contrary, young FAPs modulate the muscle healing system by stronger paracrine effects on MuSCs. Authors pin-pointed a molecular candidate in WISP1 (Wnt1 Inducible Signalling pathway Protein 1) within the secretome (i.e. the whole of cell-secreted paracrine molecules) of the injury-activated and young FAPs, as further validated in WISP^−/− mice with age-related defects in muscle regeneration; paracrine therapy via systemic administration of recombinant WISP1 in aged mice showed to restore regenerative MuSC myogenesis. Therefore, targeting the signalling cross-talk within the MuSC niche via the FAP secretome, could help rejuvenating muscle healing, while counteracting age-related decay of regenerative potential. This study provides relevant insights for cardiac repair and regeneration as well. Ageing is a leading factor for cardiovascular disease, with the heart long being considered devoid of any regenerative capacity. Disease- or injury-related compensatory mechanisms include hypertrophy of resident cardiomyocytes and organ-wide remodelling, leading to heart failure. In the last years, growing interest has been dedicated to the identification of endogenous myocardial precursors with responsive restorative potential. Several populations of cardiac progenitor cells (CPCs) have been described with putative cardiovascular differentiation capacity; despite initial enthusiasm, an increasing body of works has been questioning the efficacy of CPC myogenic potential following injury. Indeed, in the adult injured heart, CPCs have shown to preferentially commit to a fibroblastic or vascular phenotype, with the few newly generated cardiomyocytes deriving from surviving pre-existing ones.⁴ Deutsch et al.⁵ clearly showed that myocardial infarction triggers resident murine cardiac stromal cells expressing an activated enhancer for the multipotent progenitor embryonic gene Nkx2.5. Although these cells retrieve expression of stem cell- and early cardiac transcription factors, they undertake a pro-fibrotic fate, rather than differentiating into new cardiomyocytes, suggesting that genetic restoration of the embryonic programme during adulthood might not be sufficient to reinstate developmental plasticity. Yet, CPCs have demonstrated to instruct the cardiac microenvironment by modulatory signalling and support local angiogenesis after injury⁶; ex vivo administration of the CPC secretome (including extracellular vesicles) in rodent models of myocardial infarction results in cardiac function improvement with preservation of viable cardiomyocytes.⁷ Hence, CPCs are likely to be considered endogenous regulatory supporting cells, rather than myogenic precursors; they are primed by a fibrogenic signature and endowed with relevant secretory potential, thus resembling the cardiac counterpart to skeletal muscle FAPs.