Interaction between epigenetic and metabolism in aging stem cells

https://doi.org/10.1016/j.ceb.2016.12.009Get rights and content

Aging is accompanied by a decline in tissue function, regeneration, and repair. A large part of this decline is caused by the deterioration of tissue stem cell function. Understanding the mechanisms that drive stem cell aging and how to counteract them is a critical step for enhancing tissue repair and maintenance during aging. Emerging evidence indicates that epigenetic modifiers and metabolism regulators interact to impact lifespan, suggesting that this mechanism may also affect stem cell function with age. This review focuses on the interaction between chromatin and metabolism in the regulation of tissue stem cells during aging. We also discuss how these mechanisms integrate environmental stimuli such as nutrient stress to regulate stem cell function. Finally, this review examines new perspectives for regeneration, rejuvenation, and treatment of age-related decline of stem cell function.

Section snippets

Interaction between epigenetic and metabolic pathways in organismal aging

The importance of epigenetic mechanisms in controlling aging has been extensively reviewed [2, 3, 4, 5]. In this section, we will present recent studies that have uncovered intriguing connections between key chromatin regulators and metabolic pathways in the regulation of lifespan in yeast, worms, and flies. These studies help illustrate the importance of the interactions between chromatin and metabolism in the regulation of processes that may be important in cell and tissue aging. For example,

Epigenetics and stem cell aging

Epigenetic changes associated with somatic stem cell aging have been reported for multiple stem cell populations, notably hematopoietic stem cells (HSCs) and muscle stem cells (MuSCs)/satellite cells [19, 20]. In both HSCs and MuSCs, there is an age-dependent increase in the repressive histone modification H3K27me3, whereas H3K4me3, a mark associated with active genes, shows increase in breadth in HSCs but decreases slightly in intensity in quiescent MuSCs with age. In each case, the increase

Direct modulation of epigenetic regulator activity by metabolites in stem cells

While epigenetic states are clearly under multiple levels of control, their direct regulation by metabolites in a variety of cell types, including stem cells, is an area that has recently been of great interest. It is noteworthy that the co-factors important for enzymes that regulate chromatin modifications (e.g., DNA methylation/demethylation, histone acetylation/deacetylation, and histone methylation/demethylation) are metabolites whose levels are determined by the metabolic status of the

Indirect regulation of stem cell function by metabolism: effects of nutrient sensing pathways

While some key regulators of lifespan and healthspan, such as sirtuins, are directly regulated by metabolites, other crucial regulators, including the insulin-FOXO and the mTOR signaling pathways, are global integrators of cellular nutrient and metabolic status (Figure 3). The role of these pathways in the control of stem cell fate has been extensively reviewed [39]. Here, we will focus in how these pathways affect stem cell function and their changes with age, at least in part through

The role of external stimuli: effects of starvation/refeeding and high fat diets on stem cell function

The impact of metabolism on stem cell aging is suggested by the profound effect that caloric restriction has in extending lifespan. In addition, caloric excess (e.g., high fat diets) often has negative healthspan and lifespan effects [51]. Dietary changes that mimic fasting and that delay the onset of age-related pathologies are able to enhance the function of stem cells in multiple tissues [52••]. Prolonged fasting itself promotes HSC-based regeneration of the hematopoietic system [53].

Conclusion and future outlook

While exciting progress has been made in understanding how metabolic process and chromatin modifiers interact in stem cells, it is still unclear how this interaction affects stem cell function, how it is impacted by environmental stimuli, and how it changes during aging. A deeper knowledge of the interaction between chromatin regulators and metabolic processes will be critical for understanding stem cell responses to other physiological processes that impact metabolism such as circadian rhythm,

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We apologize to the authors whose work we could not cite due to space limitation. We thank Bérénice Benayoun for feedback on the manuscript. Supported by P01 AG036695 (A.B. and T.A.R.) and by the Glenn Center for the Biology of Aging (A.B. and T.A.R.).

References (72)

  • V. Boonsanay et al.

    Regulation of skeletal muscle stem cell quiescence by Suv4-20h1-dependent facultative heterochromatin formation

    Cell Stem Cell

    (2016)
  • B.A. Benayoun et al.

    H3K4me3 breadth is linked to cell identity and transcriptional consistency

    Cell

    (2014)
  • S. Vora et al.

    Next stop for the CRISPR revolution: RNA-guided epigenetic regulators

    FEBS J

    (2016)
  • T.A. Rando et al.

    Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock

    Cell

    (2012)
  • E. Verdin

    NAD(+) in aging, metabolism, and neurodegeneration

    Science

    (2015)
  • J.G. Ryall et al.

    The NAD(+)-dependent SIRT1 deacetylase translates a metabolic switch into regulatory epigenetics in skeletal muscle stem cells

    Cell Stem Cell

    (2015)
  • S.J. Mentch et al.

    Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism

    Cell Metab

    (2015)
  • N.S. Chandel et al.

    Metabolic regulation of stem cell function in tissue homeostasis and organismal ageing

    Nat Cell Biol

    (2016)
  • V.A. Rafalski et al.

    Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain

    Nat Cell Biol

    (2013)
  • M. Mohrin et al.

    Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging

    Science

    (2015)
  • A.E. Webb et al.

    Characterization of the direct targets of FOXO transcription factors throughout evolution

    Aging Cell

    (2016)
  • B.K. Kennedy et al.

    The mechanistic target of rapamycin: the grand ConducTOR of metabolism and aging

    Cell Metab

    (2016)
  • J.T. Rodgers et al.

    mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G(Alert)

    Nature

    (2014)
  • C. Lopez-Otin et al.

    Metabolic control of longevity

    Cell

    (2016)
  • O.H. Yilmaz et al.

    mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake

    Nature

    (2012)
  • S. Beyaz et al.

    High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

    Nature

    (2016)
  • S. Fusco et al.

    A CREB-Sirt1-Hes1 circuitry mediates neural stem cell response to glucose availability

    Cell Rep

    (2016)
  • N. Jiang et al.

    Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging

    Aging (Albany NY)

    (2013)
  • L.A. Warren et al.

    Transcriptional instability is not a universal attribute of aging

    Aging Cell

    (2007)
  • I.M. Conboy et al.

    Rejuvenation of aged progenitor cells by exposure to a young systemic environment

    Nature

    (2005)
  • V. Silva-Vargas et al.

    Age-dependent niche signals from the choroid plexus regulate adult neural stem cells

    Cell Stem Cell

    (2016)
  • M.A. Goodell et al.

    Stem cells and healthy aging

    Science

    (2015)
  • B.A. Benayoun et al.

    Epigenetic regulation of ageing: linking environmental inputs to genomic stability

    Nat Rev Mol Cell Biol

    (2015)
  • S. Pal et al.

    Epigenetics and aging

    Sci Adv

    (2016)
  • C.G. Riedel et al.

    DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity

    Nat Cell Biol

    (2013)
  • R.H. Houtkooper et al.

    Sirtuins as regulators of metabolism and healthspan

    Nat Rev Mol Cell Biol

    (2012)
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