Fight Aging!

In today's open access paper, researchers discuss the influence of metabolism on the aging of stem cells. Stem cells maintain tissue by providing a supply of daughter somatic cells to replace losses. Animals have evolved to minimize the risk of cancer by limiting the ability of near all cells to replicate. Somatic cells operate under the Hayflick limit, driven by loss of telomere length with each cell division, leading to senescence or self-destruction when telomeres are short. Stem cells use telomerase to maintain long telomeres and thus continually produce replacement somatic cells with long telomeres.

Unfortunately stem cell activity is reduced with advancing age, leading to a reduced production of somatic cells and the steady decline of tissue maintenance and function. The causes of this are complex, even while being energetically explored by a large portion of the broader research community. At the very high level, damage to stem cells, damage to the supporting cells of the stem cell niche, and changes in the signaling environment that cause stem cells to become more quiescent, even if undamaged. The balance of these issues appears different for different stem cell populations. Aged muscle stem cells appear functional when given a youthful environment, for example.

Metabolic Regulation of Stem Cells in Aging

Somatic stem cells integrate critical environmental inputs that inform decisions on self-renewal, differentiation, and subsequent tissue turnover. Aging is a risk factor for many diseases, and recent studies are starting to uncover the molecular mechanisms of how environmental factors, such as diet, can influence stem cell behavior over time. With aging, many adult stem cell populations accumulate damage and become impaired in their function, which leads to inefficient tissue repair and may predispose to age-associated diseases such as cancer. Although numerous studies have shown that dietary restriction confers beneficial effects on overall organismal lifespan, we are just starting to uncover the complexities of metabolic dependencies in stem cells and how the availability of specific nutrients are sensed within a heterogeneous population of stem, progenitor, and niche cells and communicated between each other. The advent of new single cell technologies has already begun to enhance our ability to resolve the complex metabolic heterogeneity and interactions that exist in certain niches, such as in the gut crypt and bone marrow.

Recent studies using single cells technologies have also revealed that seemingly uniform, terminally differentiated cells in the liver and intestinal villus have specific transcriptional metabolic profiles that are driving cell function. These differences among hepatocytes and enterocytes were largely influenced by location, proximity to nutrients, and oxygen supply within their respective tissues. In the upcoming years, as multiple single cell -omic technologies advance and integrate, we will begin to see more advanced tissue maps of transcriptional, proteomic, and metabolomic signatures of stem and progenitor cells and their corresponding niches, both under homeostatic conditions as well as during aging and other pathological states. These types of studies will also likely layer dietary patterns with other environmental factors to expand our understanding of how nutrients and systemic metabolism impact tissue homeostasis. Finally, the constant improvement and engineering of primary 3D organoid cultures will allow us to more precisely examine intrinsic and extrinsic age-associated changes, as well as measure the activity of metabolic pathways, in response to defined nutrient conditions. We will be able to incorporate and study other signals in these systems, such as cytokines, hormones, and microbial metabolites. All of these advances will conceivably lead to better strategies and therapies for tissue repair with age, while carefully avoiding interventions that may accelerate age-dependent diseases such as cancer.