When stem cells grow old: phenotypes and mechanisms of stem cell aging

Abstract

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan.

Keywords: Age-related diseases; Hematopoietic stem cells; Multicellular organisms.

Fig. 1.

Chromatin changes associated with stem cell aging. Changes in the structure and makeup of chromatin during aging have been characterized in HSCs and satellite cells. These changes include differences in the levels and distribution of chromatin-modifying enzymes (blue circles), histone modifications (green flag, activating; red flag, repressive; filled flag, increases during aging; empty flag, decreases during aging) and DNA methylation (pink star) patterns. Such changes result in regional loss of transcriptional silencing (yellow), altered cell fate decisions, decreased function and cellular senescence.

Fig. 2.

The molecular effects of caloric restriction. Caloric restriction causes reduced levels of insulin, IGF and amino acids, and increased levels of NAD⁺ and AMP. These changes are sensed by the insulin-IGF signaling (IIS) pathway, target of rapamycin (TOR), sirtuins and AMP kinase (AMPK), resulting in enhanced DNA repair, stability of the epigenome, stress resistance, oxidative metabolism and ultimately, longevity. All of these signals, sensors and responses regulate stem cell behavior. Green arrows represent interactions that promote longevity and related phenotypes, and red arrows are interactions that suppress these phenotypes.

Fig. 3.

Differences between quiescent and cycling stem cells in DNA repair and metabolism. The proliferation rate of a stem cell affects its exposure and responses to mechanisms of aging. Although quiescent stem cells are less susceptible to DNA damage, when it does occur they are more likely to utilize error-prone non-homologous end-joining (NHEJ) as a repair mechanism, whereas cycling stem cells are more likely to use homologous recombination (HR). Cycling stem cells also have higher metabolic demands than quiescent stem cells, including both higher rates of glycolysis and increased oxidative metabolism.

Fig. 4.

Asymmetric cell division as a mechanism for removing cellular damage. In budding yeast, extrachromosomal DNA, carbonylated proteins and damaged organelles are sequestered in the mother cell, allowing the daughter cell to inherit more ‘youthful’ components in a process requiring the SIR2 deacetylase (a homolog of the mammalian sirtuins). During divisions of mammalian stem cells, similar processes maintain a ‘youthful’ state, in this case in the stem cell. Such polarized divisions, which require the activity of CDC42, become less frequent with increasing age.