Fight Aging!

Investigation of the contribution of stem cells to the process of degenerative aging is a flourishing field of research. As we age our stem cell populations gradually cease their activity, spending more time in periods of quiescence, and becoming more damaged by the wear and tear of continued metabolic activity. The principal role of stem cells is to provide a supply of new cells to keep tissues in working order, and diminished supply results in growing frailty and dysfunction. This is one of the causes of disease and death due to aging.

There are reasons for optimism, however. The stem cell research field is collectively one of the largest and most active scientific institutions in the world today. At present there are many possible avenues towards the development of therapies to slow or reverse those aspects of aging that are directly caused by growing stem cell dysfunction and quiescence. Further, since so many of the first generation regenerative therapies emerging from the study of stem cells are intended to treat age-related diseases, researchers in this field have a strong incentive to find and address all of the major age-related issues associated with stem cell biochemistry. They have to tackle these challenges in order to assure the effectiveness of their stem cell treatments. That said, this is of course only one of a number of fields that must all become this energetic and well funded if we are to see significant progress towards a comprehensive toolkit of rejuvenation therapies, many of which are far removed indeed from that level of support.

It is nonetheless encouraging to see progress on a near weekly basis reported in publications and the press. The latest issue of Cell Stem Cell features a number of open access papers on the role of stem cells in aging, illustrative of a range of current directions in research. I think you'll find them interesting:

Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline?

Understanding the mechanisms driving aging may lead to innovative strategies to increase health span, an effort that would carry enormous human and economic benefit. The fact that many species (typically, though not exclusively, more slowly developing, longer-lived, and larger species) possess somatic stem cells capable of self-renewal and tissue regeneration calls into question why these organisms and their somatic stem cells do age whereas the germline apparently does not. It is also unclear how evolutionary theories of aging that are currently accepted as at least plausible can be reconciled with the biological properties of somatic stem cells.

It is proposed here that somatic stem cell maintenance mechanisms lead to preferential accumulation, rather than disposal, of damaged stem cells. On the other hand stringent selection in the germline renders this lineage seemingly immortal. Furthermore, use of glycolysis for ATP production in somatic stem cells as opposed to mitochondrial respiration in the germline suggests that mitochondria play a critical role in stem cell maintenance and gamete selection. This hypothesis is consistent with prevailing evolutionary theories of aging, and with a critical role for mitochondria in aging.

Stem Cell Aging and Sex: Are We Missing Something?

A glance at the list of the human individuals currently living over the age of 110 - supercentenarians - reveals a surefire strategy for achieving such exceptional longevity: be female. Out of the 53 living supercentenarians, 51 are female. No other demographic factor comes remotely close to sex in predicting the likelihood of achieving such an advanced age. Sexual dimorphism with respect to longevity is a characteristic of most mammals and has been recorded in human populations since at least the mid-18th century. This dichotomous capacity for resilience has inspired wide-ranging hypotheses to explain the underlying mechanisms. It also raises questions regarding the sexual dimorphism of processes known to sustain tissue regeneration and function throughout life, including adult stem cell renewal.

Most adult stem cell populations undergo an age-related decline, leading to dysfunctional tissue homeostasis, which most likely participates in defining the ultimate lifespan of the organism. Interestingly, sex-specific regulation of stem cell populations has been demonstrated for several stem cell types, and it has long been appreciated that many canonical aging pathways exhibit sex specificity. However, despite the seeming interrelationship between sex, stem cell maintenance, and aging, few studies have sought to directly explore the interaction of these three variables. Here we discuss the sexual dimorphism of adult stem cell populations and how processes regulating the aging of stem cells may also be modified by sex.

Programming and Reprogramming Cellular Age in the Era of Induced Pluripotency

Pluripotent stem cells (PSCs) are characterized by their ability to extensively self-renew and differentiate into all the cell types of the body. We propose PSCs cells as a novel model for studying human aging. Unlike traditional aging paradigms that focus on endpoints such as longevity or the restoration of regenerative capacity, PSCs allow us to monitor and manipulate molecular and cellular hallmarks of aging during both reprogramming and cell differentiation. Capturing the timing and sequence of the steps involved in cellular rejuvenation offers a unique opportunity for subsequent mechanistic studies.

The strong evidence for cellular rejuvenation during induced pluripotent stem cell (iPSC) induction indicates that many aspects of aging are reversible and may represent epigenetic rather than genetic barriers in biology. Therefore, a future is conceivable wherein it will be possible to reliably rejuvenate somatic cells without the need to move them back to pluripotency. In addition to studying rejuvenation, it will be equally important to identify novel induced aging strategies. The ability to direct both cell fate and age in iPSC-derived lineages will allow modeling of human disorders at unprecedented precision. Such studies could yield more relevant disease phenotypes and define novel classes of therapeutic compounds targeting age-related cell behaviors. The ability to program and reprogram cellular age on demand will present an important step forward on the road to decoding the mystery of aging.

Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer

The incidence of tissue dysfunction, diseases, and many types of cancer, including colorectal cancer and some types of leukemia, exponentially increases with age, and aging represents the single biggest risk factor for most cancers. However, the reasons for this aging-associated failure in tissue maintenance and the increase in cancer are poorly understood. Without a doubt, cancer is largely driven by genome dysfunction, frequently exemplified by specific genetic alterations that drive one or more specific cancer phenotypes. Overwhelming evidence indicates that the genesis and progression of cancer depend on accumulation of genetic alterations.

There is emerging evidence that aging induces changes in molecular pathways that accelerate the initiation and/or clonal dominance of mutations in stem and progenitor cells. The tight connection between aging-associated accumulation of stem and progenitor cell mutations with the failure of tissue maintenance and cancer suppression indicates a causal relationship between these factors. In addition to the cell-intrinsic mechanisms discussed here, there is increasing evidence that cell-extrinsic factors affect stem cell maintenance and possibly the selection of mutant stem and progenitor cells during aging. Likely, and potentially exciting, extrinsic candidates include aging-associated defects in the stem cell niches, alterations in the systemic/blood circulatory environment, changes in proliferative competition among stem and progenitor cells, inflammatory responses, and defects in immune surveillance of damaged cells. The delineation of this interplay of cellular and molecular mechanisms that contribute to the initiation and selection of stem and progenitor cell mutations in the context of aging will undoubtedly help the development of therapies aiming to improve early detection, prevention, and risk assessment of aging-associated diseases, organ dysfunction, and cancer.