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.

Altered modulation of lamin A/C‐HDAC2 interaction and p21 expression during oxidative stress response in HGPS

“…We suggest that senescent cells accumulate in HGPS after several stress events due to failure to restore p21 levels and properly reorganize heterochromatin. It has been reported that organism senescence is related to the number of senescent cells, especially in stem cell niches (Bhatia‐Dey, Kanherkar, Stair, Makarev, & Csoka, 2016). Thus, altered HDAC2 functionality may directly contribute to the accelerated aging process in laminopathic patients.…”

Engineering a human skin equivalent to study dermis remodelling and epidermis senescence in vitro after UVA exposure

“…Indeed, here, we demonstrate for the first time in vitro that UVA‐induced cellular and extracellular senescence was reflected in the simultaneous decline of epidermal germinative potential and collagen network assembly. It is reasonable to argue that early senescence phenomena described in our work are quite similar to the initial mechanisms that in vivo lead to photoaging of human skin (Bhatia‐Dey et al, ; Keyes et al, ; Keyes & Mills, ; Su et al, . In order to study the biological relevance of our skin model for use in photobiological studies, we assessed first of all the oxidative damage UVA induced.…”

“…The UVA‐induced oxidative stress in epidermal compartment induces stem cell damage that, in turn, is responsible of epidermal senescence (Panich, Sittithumcharee, Rathviboon, & Jirawatnotai, ; Youn et al, ). Cellular senescence is a form of irreversible growth arrest and apoptotic resistance and represents one of the main causes of photoaging (Bhatia‐Dey, Kanherkar, Stair, Makarev, & Csoka, ; Campisi & d'Adda di Fagagna, ). The ultimate visible effects of photoaging are irregular skin pigmentation, laxicity, and wrinkles (Fisher et al, ; Helfrich, Sachs, & Voorhees, ).…”

A unified model of dementias and age‐related neurodegeneration

“…76 Cell senescence was first described >50 years ago, 77,78 and its implications for age-related disease were outlined in both the lay 79 and medical literature >20 years ago 80,81 and repeatedly implicated since. 82 Cell senescence was first shown to correlate with, [83][84][85] then to be the causal result of, telomere shortening and amenable to resetting in vitro. 86 Subsequently, resetting of telomere length was shown to reset function in aging human tissue both ex vivo 87 and in vitro, 88,89 further supporting cell senescence as a viable point of clinical intervention.…”