Age-related declines in stem cell function: Molecular insights and future therapies

Stem cells are fundamental units that support tissue homeostasis throughout life, thus, progressive loss of function with aging would result in defective maintenance and regeneration of tissues, which in turn increases vulnerability to age-associated diseases. This review summarizes the potential contributors such as telomere shortening, DNA damage accumulation, epigenetic changes and mitochondrial dysfunction to age-associated defects in stem cell function. We discuss the interactions of these intrinsic factors with changes in the stem cell niche, including blood-derived inflammatory signals and changes in the extracellular matrix that contribute to stem cell exhaustion. Despite this local accessibility and its known role in regeneration, our knowledge about the age-related loss of tissue-specific regenerative potential is limited largely to age-related changes in specific stem cell populations, including hematopoietic, mesenchymal, neural, muscle satellite and intestinal stem cells, and highlights the potential for tissue-specific regenerative impediments. Further, new therapeutic strategies against stem cell exhaustion are discussed, such as caloric restriction, genetic and epigenetic reprogramming, senolytics, stem cell transplantation, and mitochondrial-targeted therapies. It also discusses challenges in tumorigenesis, immune rejection, and long-term efficacy. The review then ends with a reminder of the importance of ongoing studies for generating applicable treatments to prolong healthy life and promote regenerative responses. The present extensive synthesis is intended to assist further regenerative medicine efforts by presenting the most promising therapies to counteract aging effects on stem cells.