Cellular Senescence as the Causal Nexus of Aging

Abstract

In this paper we present cellular senescence as the ultimate driver of the aging process, as a "causal nexus" that bridges microscopic subcellular damage with the phenotypic, macroscopic effect of aging. It is important to understand how the various types of subcellular damage correlated with the aging process lead to the larger, visible effects of anatomical aging. While it has always been assumed that subcellular damage (cause) results in macroscopic aging (effect), the bridging link between the two has been hard to define. Here, we propose that this bridge, which we term the "causal nexus", is in fact cellular senescence. The subcellular damage itself does not directly cause the visible signs of aging, but rather, as the damage accumulates and reaches a critical mass, cells cease to proliferate and acquire the deleterious "senescence-associated secretory phenotype" (SASP) which then leads to the macroscopic consequences of tissue breakdown to create the physiologically aged phenotype. Thus senescence is a precondition for anatomical aging, and this explains why aging is a gradual process that remains largely invisible during most of its progression. The subcellular damage includes shortening of telomeres, damage to mitochondria, aneuploidy, and DNA double-strand breaks triggered by various genetic, epigenetic, and environmental factors. Damage pathways acting in isolation or in concert converge at the causal nexus of cellular senescence. In each species some types of damage can be more causative than in others and operate at a variable pace; for example, telomere erosion appears to be a primary cause in human cells, whereas activation of tumor suppressor genes is more causative in rodents. Such species-specific mechanisms indicate that despite different initial causes, most of aging is traced to a single convergent causal nexus: senescence. The exception is in some invertebrate species that escape senescence, and in non-dividing cells such as neurons, where senescence still occurs, but results in the SASP rather than loss of proliferation plus SASP. Aging currently remains an inevitable endpoint for most biological organisms, but the field of cellular senescence is primed for a renaissance and as our understanding of aging is refined, strategies capable of decelerating the aging process will emerge.

Keywords: aging; august weismann; causal nexus; germline; immortality; mortality; proliferation; senescence.

FIGURE 1

The evolution of cellular diversity as the origin of cellular senescence. Pandorina morum on the left, which is immortal, has a single cell type; whereas the mortal Volvox minor on the right has two distinct cell types representing the immortal germ line and the mortal soma in the same multicellular organism. Only the immortal germline cells in Volvox can produce the next generation (Figure adapted from West, 2003).

FIGURE 2

The dichotomy of germ line and soma: organismal diversity. The figure represents the evolution of complex organisms from simpler forms through the immortal germline. Each species is capable of self-propagation only through the germ line, and this has evolved and given rise to increasingly complex organisms from the simple organism like Volvox to the most complex such as Homo sapiens. It represents the co-existence of cellular immortality and mortality in the same organism (Figure adapted from West, 2003).

FIGURE 3

The dichotomy of germ line and soma: aging and neoplastic transformation. Totipotent embryonic stem cells give rise to both germ cells and somatic stem cell progenitors with defined self-renewal potential. Somatic progenitors divide and proliferate into tissue-specific terminally differentiated cells with limited self-renewal potential that decreases with age, and they enter senescence in response to external and internal cues. The growing population of senescent cells lead to withered tissue and organismal aging, but deregulation of proliferation arrest as well as secretion of proinflammatory cytokines has pro-oncogenic effects that can trigger neoplastic transformation, evident with the appearance of cancer stem cells; their further aggressive division leads to tumorigenesis.

FIGURE 4

Senescence is a tumor suppression mechanism, by blocking proliferation of cancer cells, and promotes aging via loss of macroscopic structure and “inflammaging”. Cancer cells must bypass senescence to continue proliferating. A proliferating cell undergoes stress from, e.g., damaged telomeres and oxidation, leading to activated oncogenes. This leads to cellular senescence, characterized by loss of proliferation, and activation of SASP and inflammation. In combination with immune clearance this is a tumor suppression mechanism. Cancer cells must somehow bypass senescence, i.e., through inactivation of p53 and pRb and/or activation of telomerase, in order to continue proliferating.

FIGURE 5

Cellular senescence and aging. The organismal life span is controlled by internal and external factors inducing senescence and therefore, proliferation arrest. The text lists molecular and physiological triggers that may lead to: telomere attrition, aneuploidy, DDR response, epigenetic modulations, and mitochondrial dysfunction; these are causes of senescence manifested as either loss of cellular proliferation and emergence of the senescent associated secretory phenotype (SASP) in dividing cells, or simply SASP alone in non-dividing cells.

FIGURE 6

Damage leads to causal nexus leads to effects. In different species the causes of cellular senescence may be similar, but have different magnitudes. For example, in mice (A) DNA damage/Tumor suppressor activation may be a major factor, whereas in humans (B), telomere erosion may have a greater effect because humans have much shorter telomeres than mice. In both species, accrued, and unrepaired damage to the cellular genome, epigenome, and organelles (causes) is finally manifested in the visible phenotype, evident as aged features of the organism, such as organ dysfunction, loss of structural integrity, and physiological and anatomical changes (effect). The link between cause and effect, the causal nexus, is cellular senescence. Additionally, it has been shown that in mice, blocking cell division alone, in the absence of any molecular damage, can induce premature Progeria-like aging.