Attempting a Unified View of Aging and Loss of Regenerative Capacity


Pioneer Founding member

Today's open access paper from the AgeX Therapeutics folk discusses a conceptual framework for looking at aging and loss of regeneration in a unified way across: (a) evolutionary differences between highly regenerative lower species such as hydra and less regenerative higher species such as mammals, (b) the loss of regenerative capacity over the course of embryonic development, and (c) the loss of regenerative capacity that occurs with aging in individuals. It covers a lot of ground, and even the summaries could do with a shorter summary.

In essence this all ties back to the work being done at AgeX Therapeutics and elsewhere on the potential uses of induced pluripotency to produce regenerative therapies. The discovery that cells can be reprogrammed into what are essentially embryonic stem cells, known as induced pluripotent stem cells, was made a little over a decade ago. One of the most interesting outcomes of this process is that various markers of age found in the cells in old tissue are reversed. Damaged mitochondrial are cleared, restoring function. Epigenetic decorations characteristic of age are removed. A number of groups are working on ways to very carefully induce reprogramming-like outcomes in cells in the body in order to repair mitochondrial function and restore more youthful behavior.

This clearly cannot fix everything. It won't reverse stochastic nuclear DNA damage, for example. Further, since youthful cells cannot clear many of the forms of persistent metabolic waste that accumulate in and around long-lived cells, we should not expect this to greatly impact cross-linking or issues with dysfunctional lysosomes. We do know that mitochondrial dysfunction is very important in aging, however. It is implicated in the progression of many age-related conditions, particularly those of energy-hungry tissues such as the brain and muscles. It is worth chasing approaches that might effectively restore lost mitochondrial function. The major caveat here is cancer, of course. Methods of inducing pluripotency must be accomplished with great care.

Toward a unified theory of aging and regeneration

The advent of cell biology in the 19th century led to August Weismann's insightful hypothesis that heredity is transmitted by cells belonging to an immortal germ line, and that in most cases, the evolution of complex somatic cells and tissues is associated with a loss of immortal regeneration (somatic restriction) that results in aging. Thus, he correctly predicted the limited lifespan of cultured somatic cells due to cellular senescence. In 1957, George Williams hypothesized that aging evolved through a process of antagonistic pleiotropy, where traits benefitting fecundity early in life are selected for even though they simultaneously lead to age-related deterioration later in life. According to an emerging consensus view of the evolution of aging, primitive organisms showing negligible senescence have not traversed the Weismann barrier (loss of immortality and regeneration), while human somatic cell types cross the barrier early in development leading to downstream age-related change.

While certain evolutionarily primitive metazoans, and perhaps some vertebrates, show no evidence of aging, mammals typically show an exponential increase in the risk of mortality with age. Mammalian aging can be viewed as a global developmental program in many cells and tissues in the body wherein somatic cells are progressively restricted in their capacity for immortal regeneration. Accordingly, these steps begin with the repression of the expression of the catalytic component of telomerase TERT resulting in the antagonistic pleiotropic effect of decreased risk of cancer early in life but a finite replicative lifespan of somatic cells leading to cell and tissue aging later in life. Other genes such as TRIM71 also appear to be repressed at or around the time of the pluripotency transition, and the loss of expression may also play a role in restricting cell division. Moreover, subsequent developmental restrictions may also play a role in the cadence of developmental changes that repress tissue regeneration following the completion of organogenesis and subsequent growth. In summary, widespread gene expression changes, like TERT repression, occur early in the life cycle, in many tissues within the body, and these early changes may have an antagonistic pleiotropic effect later in life leading to tissue disrepair associated with aging.

Increasingly the theoretical framework underlying modern aging research is that progressive developmental transitions occur early in the life cycle that impact tissue regeneration and therefore aging in the body. The theory of somatic restriction highlights the dichotomy of the immortal regenerative potential of the germ-line compared to the terminal mortal phenotype of most differentiated somatic cell types. The theory posits that somatic restriction occurs progressively in stages (pluripotency to differentiating embryo, embryo to fetal, fetal to neonate, and neonate to fully grown adult) and that many of these transitions occur globally in multiple organ systems. This conceptual framework provides a context for more detailed analytical studies of developmentally-regulated molecular pathways that were selected for reproductive fitness early in the life cycle, but result in homeostatic decline and failure of organ systems in aging adults (antagonistic pleiotropy). We conclude that modern molecular approaches to regenerative medicine such as reprogramming cells to pluripotency or partially reprogramming to induce tissue regeneration effectively reverse most markers of aging and have significant potential for clinical application in aging.