How stem cells age and why this makes us grow old

Key Points

  • Cancer and ageing appear to represent the failure or success, respectively, of vital tumour-suppressor mechanisms that rely on the activities of telomere shortening and the activation of the cyclin-dependent kinase inhibitor p16INK4a and the tumour suppressor p53.

  • Evidence suggests that these tumour-suppressor molecules exert pro-ageing and anti-cancer functions in discrete compartments of self-renewing cells (tissue-specific stem cells) that are present in adult mammalian tissues.

  • Adult stem cells appear to accumulate DNA damage with ageing as a result of extrinsic exposures, telomere shortening and/or replicative stress associated with homeostatic proliferation.

  • Accumulated DNA damage in stem-cell compartments can be oncogenic, or can engage tumour-suppressor mechanisms such as cellular senescence and apoptosis.

  • Mice with dysfunctional telomeres or increased activity of p53 or p16INK4a demonstrate an accelerated appearance of ageing phenotypes, whereas loss of p16INK4a can attenuate the decline in stem-cell function that is associated with physiological ageing.

  • Loci near the INK4/ARF locus on human chromosome 9p21 are associated with an increased incidence of ageing-associated conditions in humans such as frailty, type 2 diabetes mellitus and coronary artery disease.

Abstract

Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a, may also induce an unwanted consequence: a decline in the replicative function of certain stem-cell types with advancing age. This decreased regenerative capacity appears to contribute to some aspects of mammalian ageing, with new findings pointing to a 'stem-cell hypothesis' for human age-associated conditions such as frailty, atherosclerosis and type 2 diabetes.

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Figure 1: How stem cells age.
Figure 2: Proliferation of β-cells with age.
Figure 3: Fates of damaged stem cells.
Figure 4: SNPs and age-related phenotypes at the INK4a/ARF/INK4b locus on human chromosome 9p21.

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Acknowledgements

We thank E. Sahin, J.-H. Paik, T. Letai and K. Mohlke for critical reading and advice on the manuscript. R.A.D. is a director, co-founder and scientific advisor of AVEO Pharmaceuticals, Inc. in Cambridge, Massachusetts, USA, and is an American Cancer Society Research Professor and an Ellison Medical Foundation Senior Scholar. This work was supported by grants from the Sidney Kimmel Foundation for Cancer Research (N.E.S.), the Ellison Medical Foundation (N.E.S. and R.A.D.), the American Federation of Aging Research (N.E.S.), the Burroughs Wellcome Fund (N.E.S.) and the US National Institutes of Health (R.A.D.). R.A.D. is supported by the LeBow Fund to Cure Myeloma and the Robert A. and Renee E. Belfer Foundation Institute for Innovative Cancer Science.

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DATABASES

OMIM

ataxia telangiectasia

Hutchinson–Gilford syndrome

type 2 diabetes mellitus

Werner syndrome

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Glossary

Forkhead transcription factor class O

(FOXO). One of a family of evolutionarily conserved transcription factors that are linked to lifespan regulation in lower systems and to stem-cell maintenance in mice. The FOXO proteins are thought to exert these effects by regulating the expression of genes involved in apoptosis, proliferation, glucose metabolism, DNA repair, regulation of reactive oxygen species and other diverse cellular processes.

Self-renewal

The capacity of replicating stem cells to generate daughter cells with the same biological and molecular profile that endows continued renewal potential. This can occur either asymmetrically when a stem cell produces another stem cell and a more differentiated daughter cell, or symmetrically when stem-cell division gives rise to two identical stem cells. Importantly, in mature organ systems, most cell-division activity that is responsible for tissue maintenance and expansion is not self-renewing.

Progeny

Along with progenitor cells, these are relatively undifferentiated cell types that are derived from asymmetric stem-cell division and lack the capacity to self-renew.

Senescence

A specialized form of growth arrest induced by various stressful stimuli including loss of telomere function, reactive oxygen species, some forms of DNA damage and activation of certain oncogenes or reactivation of tumour-suppressor genes. Senescence is characterized by several markers such as senescence-associated-β-galactosidase, alterations in chromatin structure (senescence-associated heterochromatic foci) and a marked increase in the secretion of several cytokines and other bioactive molecules (senescence-associated secretory phenotype).

Tissue-specific stem cell

A specialized cell found in many tissues of adults. These cells can replace themselves through self-renewal and are generally multipotent, in that they can give rise to progeny that can differentiate into multiple different cell types of the associated organ.

Multipotency

The ability to give rise to differentiated progeny of different specialized subtypes. However, some self-renewing cells (for example, pancreatic β-cells) have a narrow potential for differentiation, generating progeny similar to the parental cell. This type of self-renewing cell is termed a 'unipotent progenitor', which can be viewed as a special stem-cell subtype, at least in terms of long-term proliferative capacity. For convenience, in this Review the term 'stem cell' is applied to both types of adult self-renewing cells.

Telomere

A nucleoprotein complex at the end of chromosomes that maintains chromosomal integrity. It consists of many double-stranded 5′-TTAGGG-3′ repeats, a 3′-single-stranded overhang and associated telomere-binding proteins, which together generate a capped structure that is impervious to the actions of complexes that repair DNA damage.

Telomerase

A ribonucleoprotein complex that extends the ends of telomeres after replication by using telomerase reverse transcriptase (TERT) and an RNA template (TERC) that is part of the enzyme complex.

Single nucleotide polymorphism

A common, single-base difference in a gene among individuals within a species.

Frailty

A clinically validated, functional measure used in clinical geriatrics. It is scored as a continuous variable using a series of routine, easily measured tests such as gait speed. Frail individuals are less able to live independently, are more likely to harbour co-morbid illnesses, and exhibit increased mortality.

Linkage disequilibrium

(LD). A measure of genetic associations between alleles at different loci, which indicates whether allelic or marker associations on the same chromosome are more common than expected. Loci are generally considered to be in strong LD if their correlation is higher than a pre-defined cut-off (for example, 0.8).

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Sharpless, N., DePinho, R. How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8, 703–713 (2007). https://doi.org/10.1038/nrm2241

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