Growing evidence supports the antagonistic pleiotropy theory of mammalian aging. Accordingly, changes in gene expression following the pluripotency transition, and subsequent transitions such as the embryonic–fetal transition, while providing tumor suppressive and antiviral survival benefits also result in a loss of regenerative potential leading to age-related fibrosis and degenerative diseases. However, reprogramming somatic cells to pluripotency demonstrates the possibility of restoring telomerase and embryonic regeneration pathways and thus reversing the age-related decline in regenerative capacity. A unified model of aging and loss of regenerative potential is emerging that may ultimately be translated into new therapeutic approaches for establishing induced tissue regeneration and modulation of the embryo-onco phenotype of cancer.
Aging is often defined as a progressive deterioration of an organism over time, wherein the risk of morality increases exponentially with age in the postreproductive years. Although everyday environmental risks from predation or infectious disease (e.g., stochastic risks) necessarily lead to increased mortality over time, they are not considered core to the definition of the aging process per se. Thus, an important criterion of aging is that it encompasses virtually every somatic tissue type, including the gonads (though not necessarily the germ-line cells themselves, given their role in potentially perpetuating the species). In order to distinguish the aging process from damage that occurs stochastically over time, Benjamin Gompertz described aging as a process leading to an exponential increase in mortality with time, that is, Rm = R0eat where ‘Rm’ represents the probability of mortality between ages ‘t’ and ‘t + 1’. Accordingly, ‘R0’ is a constant, while ‘a’ represents an exponential parameter corresponding to the rate of increase of mortality with age. Diverse species exhibit wide variations in the rate of aging as high as 50-fold, and some species even show a negligible rate of aging as determined by Gompertz equation. However, the similarities in the aging process between species and within tissues of an individual support the conclusion that what we commonly call aging is the result of a series of developmentally timed processes occurring in somatic tissues.
The pathogenesis of aging, like the relatively complex etiology of cancer, is commonly viewed as being rooted in multifaceted processes intrinsic to somatic cells along with additional tissue-specific influences, inherited genetic predispositions and environmental factors. However, premature aging disorders such as Hutchinson–Gilford syndrome (progeria) and Werner syndrome showing the premature appearance of various age-related changes such as graying and loss of hair, coronary heart disease, stroke and osteoporosis lend support to an intrinsic genome-based pacing mechanism underlying aging. In addition, these naturally occurring aging disorders provide evidence that certain molecular pathways may alter the time course of the aging in multiple organ systems, suggesting that similar pathways may underlie aging in numerous somatic tissue types.
Additional insights into the molecular biology of aging can be gleaned from studies of segmental (tissue-specific) genetic predispositions as well as those comparing the genotypes of individuals with varied lifespan phenotypes. The use of genome-wide gene association studies has identified loci such as those near APOE, CHRNA5, ANRIL, LPA and FTO as being correlated with a long lifespan. However, identical twin studies suggest that environmentally induced epigenetic effects potentially play an important role in the onset of age-related disease as well. Therefore, despite recent progress in understanding the biology of aging, the field remains largely fragmented due to the lack of a central organizing hypothesis that could provide a framework for investigating how basic upstream biological processes regulate the timing of age-related changes in tissues and the influence of these changes on the onset of age-related degenerative disease.
The goal of this review is to assemble diverse observations about the etiology of aging into a more unified mechanistic model. Thus, we suggest that numerous genetic, environmental and metabolic perturbations alter the rate of aging by shifting the balance of euchromatin/heterochromatin in regulatory regions of the genome leading to either more permissive or more restrictive patterns of regenerative gene expression. Moreover, we propose that these changes in regenerative gene expression occur in a series of developmentally timed transitions that occur globally in many cell types and in various tissues of the body and that these changes impact multiple hallmarks of both aging and cancer. Using an historical perspective, we will review these developmentally timed transitions from the perspective of the loss of germ-line immortality in somatic cells and the changes in regenerative gene expression (antagonistic pleiotropy) leading to the progressive restriction of regenerative capacity and the subsequent effects on aging. Finally, we will discuss the epigenetic nature of these transitional changes that lead to aging and how their reversal during reprogramming suggests the possibility of restoring regenerative capacity to aging tissues and organs using an approach we have termed induced tissue regeneration (iTR).
Somatic restriction & antagonistic pleiotropy
In the 19th century, the German naturalist August Weismann described the elegant hypothesis that heredity is transmitted through an immortal lineage of cells commonly designated the ‘germ line’. This logically led to his proposal that since somatic cells do not carry their hereditary information forward to the next generation, they have no need for the capacity to replicate indefinitely. In other words, somatic cells are disposable from the viewpoint of evolution because there is no selective pressure for traits that would lead to their immortal replication. He therefore laid out the prediction that “death takes place because a worn-out (somatic) tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting, but finite”.
Weismann proposed that the loss of immortal replication in somatic cells (one example of somatic restriction) associated with aging resulted from the loss of traits that were not evolutionarily advantageous (a passive process). In contrast, the evolutionary biologist George Williams proposed a model of antagonistic pleiotropy as a likely mechanism in which aging was under active selection. In his model, certain genetic traits have pleiotropic effects throughout the lifespan. Accordingly, natural selection necessarily increases the probability of those traits that lead to increased fecundity, therefore, once reproduction has occurred there is very little selective pressure to eliminate these same traits even if they exert deleterious effects on fitness or viability. As a result, the two outcomes are antagonistic, such that natural selection favored traits that led to the limited replication and regeneration of the soma despite potentially deleterious effects later in life (i.e., aging) because these same traits improved reproductive fitness early in life.
The Weismann and Williams hypotheses are not mutually exclusive. Indeed, both hypotheses have grown in acceptance since they were first published and as a result, it is now commonly accepted that mammalian aging is likely the result of a developmental program wherein somatic cells progressively lose the traits of immortal proliferation and regeneration (somatic restriction) and that such restriction is the result of active selection for increased reproductive fitness. Accordingly, selection for traits that decrease the risk of oncogenesis or increase resistance to genomic instability from endogenous retroviral elements would likely increase reproductive fitness but could also contribute to the decline of regenerative potential that is observed in later life.
The restriction of the twin traits of immortal proliferation and regeneration is designated as the ‘Weismann barrier’ herein as shown in Figure 1. Accordingly, Weismann’s prediction that a worn-out tissue cannot forever renew itself was shown to be the case in many vertebrate species wherein scarless regenerative potential is repressed shortly after embryogenesis. In contrast, simple unicellular organisms such as Tetrahymena display replicative immortality, and a few primitive invertebrates such as hydra and planaria show no evidence of aging as determined by an exponential rise in the risk of mortality with time. However, in general, advanced multicellularity without cancer required a phenotype that confined continual renewal to the germ line while restricting the regenerative capacity of somatic cells and tissues. As a result, as multicellular organisms evolved to even greater complexity their regenerative capacity became increasingly restricted, and as we propose herein, the restriction may occur globally in developmental stages and include numerous cell and tissue types. Thus, nearly all mammals, including humans, repress replicative immortality in somatic cells early in embryogenesis followed by a subsequent loss of regenerative potential after embryonic development is essentially complete. This loss of both immortality and regenerative potential defines the Weismann barrier (shown as red line in Figure 1).
The somatic restriction model predicts that organisms that retain juvenile properties throughout life would also retain enhanced regenerative capacity because they would never completely traverse the Weismann barrier. Accordingly, support for the model that the profound regenerative potential of primitive metazoans is retained from early ontogeny comes from studies in amphibians such as the urodeles. For example, axolotls live their adult lives in an arrested larval stage (paedomorphosis) due to the lack of appropriate thyroid hormone signaling. These unusual animals show a profound regenerative potential in diverse tissues such as forebrain, jaw and heart. In addition, they are even capable of regenerating amputated limbs through the formation of a limb bud-like blastema, a phenomenon designated as epimorphic regeneration. Moreover, the observation that other anuran larvae (e.g., Xenopus) exhibit significant regenerative potential that is subsequently lost with metamorphosis supports the view that the retention of embryonic traits causes epimorphic regeneration in urodeles. Furthermore, there are additional models provided by various species that retain regenerative potential into adulthood such as hemimetabolous insects that show an extended nymph-like state. However, it is important to note that repeated injury to axolotls eventually leads to defective regeneration suggesting that while they may retain the profound regenerative potential of the larval state and appear to express telomerase, they may not have sufficient telomerase activity to regenerate indefinitely. Therefore, urodeles, unlike certain more primitive organisms like planaria and hydra, do not completely escape the Weismann barrier (Figure 1). The lack of telomerase as well as other insults to the genome ultimately leads to cellular senescence, which profoundly affects regenerative capacity and tissue homeostasis later in life.