Aging is an accelerating process, in which new symptoms of degeneration appear ever faster as the decline progresses. This is characteristic of the aging of any complex system, in that damage to component parts - and the dysfunction that results - tends to produce further damage and dysfunction. To pick one example of many in human biochemistry, cross-linking in the extracellular matrix causes stiffening of blood vessels, which in turn causes hypertension, which in turn causes pressure damage to delicate tissues. Or accumulation of amyloid-β in the brain leads to accumulation of tau that in turn causes cell death and dementia. Thousands of such chains of cause and effect can be found in human aging, few of which are catalogued end to end and in all their detail. The roots of aging and the causes of mortality at the ends of aging are fairly well mapped, but the complexity in between is still a matter of a few paths through a dark forest.
The lack of understanding of the details of the progression of aging, how metabolism is disrupted, and how and why that produces the next form of damage and dysfunction in the chain of cause and consequence, is one of the reasons why it is a slow and expensive process to attempt to alter metabolism to be more resilient. That is true even given the easily established altered states of metabolism, such as that produced by calorie restriction, in which aging is modestly slowed. Metabolism is ferociously complex and incompletely understood. It is thus better to focus on the causes of aging, those forms of damage that arise in the normal operation of youthful metabolism, and are simply side-effects of that operation. If those initial, root cause forms of damage can be prevented or periodically repaired, then it doesn't much matter how they go on to cause aging.
The accumulation of senescent cells is one of the root causes of aging. Even if there were no other causes of aging, cellular senescence would still kill us given time. Senescent cells are constantly created when cells reach the Hayflick limit, or suffer mutational damage, or are exposed to other excessive stresses. Near all self-destruct, and near all that fail in that are instead destroyed by the immune system. A tiny minority remain, to generate a potent mix of signals known as the senescence-associated secretory phenotype. This generates chronic inflammation, disrupts the nearby structure of tissues, and, perhaps worse of all, encourages other cells to become senescent as well. This latter behavior makes sense given the tasks that senescent cells have evolved to carry out, meaning suppression of cancer by preventing at-risk cells from replicating further, steering embryonic growth, and regeneration of injuries, but it also makes their contribution to aging that much worse.
Cellular senescence is thus its own self-contained accelerating process of aging. The more senescent cells present in tissue, the more likely it is that other cells will become senescent in response to stresses or damage. This is yet another reason to prioritize the distribution and further development of safe and effective senolytic therapies capable of selectively destroying senescent cells. These errant cells are in effect actively maintaining a state of age-related dysfunction through their signaling. Removing them is a form of rejuvenation, demonstrated in animal studies, and in the process of being further demonstrated in human clinical trials.
Senescent cells accumulate in many tissues during aging. Genetic or drug-mediated specific ablation of senescent cells ameliorates a wide range of age-associated disabilities and diseases in mice. Cell senescence can be triggered by replicative exhaustion or stressors, specifically oncogenic and DNA-damaging stress. Moreover, pre-existing senescent cells in vitro are capable of inducing a senescent phenotype in surrounding bystander cells via integrated ROS- and NF-κB-dependent signalling pathways. It has been suggested that this senescence-induced bystander senescence might be a relevant trigger of senescent cell accumulation in vivo, based on focal clustering of senescent cells in old mouse livers and of SASP-mediated accumulation of senescent cells around pre-neoplastic lesions.
In accordance, autologous transplantation of senescent fibroblasts into healthy knee joints resulted in the development of an osteoarthritis-like condition in mice. Very recently, it was shown that intraperitoneal transplantation of relatively low numbers of senescent cells caused persistent physical dysfunction in mice, indicating that senescent cells can induce a deleterious bystander effect in vivo. However, direct evidence that transplanted or pre-existing senescent cells do induce senescence in surrounding tissues is still weak.
The impact of cell senescence for aging of skeletal muscle and the dermal layer of the skin has been questioned because the major cell types are slowly dividing (dermal fibroblasts) or not dividing at all (myofibres). However, the DNA damage response (DDR) induces a senescence-like phenotype in postmitotic cells like neurons or retinal cells. In the dermis, accumulation of fibroblasts with telomere dysfunction and other senescence markers has been observed in different mammalian species. In mouse skeletal (gastrocnemius) muscle, expression of various senescence markers increased with age and decreased after selective ablation of p16-expressing presumably senescent cells.
After observing increased frequencies of multiple senescence markers in aging myofibres, we xenotransplanted small numbers of senescent human fibroblasts into mouse skeletal muscle and skin. Bioluminescent and fluorescent labelling enabled tracking of the injected cells in vivo for at least 3 weeks as well as their identification in cryosections in situ. We found that mouse cells surrounding the injection sites showed increased frequencies of multiple senescence markers when senescent cells (but not non-senescent cells) were xenotransplanted. Comparing senescent cell accumulation rates in normal and immunocompromised mice under either ad libitum feeding or dietary restriction enabled separate estimations of bystander-dependent versus cell-autonomous senescent cell accumulation, indicating a significant and possibly major contribution of the bystander effect. Adjacent to injected senescent cells, the magnitude of the bystander effect was similar to the increase in senescence markers in myofibres between 8 and 32 months of age.