Cellular senescence is one of the causes of aging. Cells become senescent in response to a variety of circumstances, the most common of which is when a somatic cell reaches the Hayflick limit on replication. Senescence also arises as a result of damage, to shut down cells that might become cancerous. Senescent cells cease to replicate, issue inflammatory signals that attract immune cells to destroy them, and usually self-destruct via programmed cell death mechanisms in any case. The problem with cellular senescence arises from the tiny fraction of senescent cells that evade destruction and linger, polluting surrounding tissue with inflammatory and other signals that evolved for short-term benefit only. When present over the long term, the signals secreted by even a comparatively small number of senescent cells will significantly degrade tissue structure and function, disrupt regeneration, and produce chronic inflammation. This accelerates the development and progression of near all common age-related diseases.
The targeted destruction of senescent cells has been well proven as a rejuvenation therapy in mice in recent years, and human trials are underway for the first senolytic drugs capable of achieving this goal. These initial drugs will be improved upon considerably in the years ahead, as they have side-effects, and only destroy half of the senescent cell burden in some tissues at best, but I expect them to nonetheless produce sizable and broad benefits in older people. Senolytic treatments are a form of repair, clearing away harmful cells that actively maintain a a state of greater dysfunction.
While forging ahead to bring benefits to tens of millions of patients as soon as possible is absolutely the right thing to be doing, there yet remains a great deal to accomplish and investigate as the field expands. On the clinical side of the fence, there are no good commercial assays that quickly and cost-effectively show senescence levels in human tissue, for example. On the scientific side of the fence, it is far from clear as to whether there exist significantly different classes of senescence with meaningful differences in activity and vulnerability to particular senolytic mechanisms. Cataloging past a handful of biomarkers and tissues has barely started. There is also the topic of today's paper, which is the degree to which the presence of lingering senescent cells increases with age because the immune system becomes compromised and falters in its surveillance. Killing senescent cells is a lot easier than restoring the immune system to youthful function, but when that goal is achieved, to what degree will senescence be purged from tissues? The open access paper here is an interesting first attempt to look at the size of this effect.
Cellular senescence, a central component of aging, is a cell-intrinsic stress response programmed to impose stable cell-cycle arrest in damaged cells, thus preventing them from propagating further damage in tissues. Normally, a sequence of events leads to the clearance of senescent cells and allows regeneration of the tissues that harbor them. In advanced age, however, the efficiency of this process may be compromised, as suggested by the tendency of senescent cells in the tissues of old individuals to accumulate. This accumulation is reportedly conserved across different species, including rodents, primates, and humans. Under such conditions, the beneficial cell-autonomous role of senescence might be outstripped by a negative impact of senescent cells on other cells, an effect mediated via the senescence-associated secretory phenotype (SASP), which has marked pro-inflammatory characteristics.
Senescent cells are subject to immune surveillance by multiple components of the immune system. Senescent cells attract and activate immune cells and serve as highly immunogenic targets for immune clearance. The immune response against senescent cells varies between different pathological conditions. For example, in fibrotic livers senescent cells derived from activated hepatic stellate cells are cleared by natural killer (NK) cells, whereas senescent pre-malignant hepatocytes are eliminated via the adaptive immune system. In other pathological conditions, for example in the case of dysplastic nevi, immune clearance does not occur and senescent cells persist for years. In the context of aging, it is not known to what extent the immune system participates in regulating the number of senescent cells, and whether age-related impairment of immune function contributes to the accumulation of senescent cells in old individuals.
Perforin, a pore-forming protein found in intracellular granules of effector immune cells, is an important mediator of immune cytotoxicity. Upon degranulation, perforin-formed pores enable granzyme penetration and caspase activation to induce apoptosis of the target cell. Perforin-mediated granule exocytosis (but not death-receptor-mediated apoptosis) is essential for the immune surveillance of senescent cells, and disruption of this pathway leads to the accumulation of senescent cells in damaged livers. To investigate the consequences of impaired immune surveillance of senescent cells in aging, we followed the aging process in mice in which granule-exocytosis-mediated apoptosis was disabled as a result of perforin gene knockout (Prf1-/-).
Our data indicates that compared to wild-type (WT) mice, Prf1-/- mice accumulates more senescent cells in their tissues with age. The accumulation of senescent cells in these Prf1-/- mice is accompanied by a progressive state of chronic inflammation, followed by increased tissue fibrosis and other types of tissue damage, as well as compromised organ functionality. The poor health of old Prf1-/- mice is associated with fitness reduction, weight loss, kyphosis, older appearance, and shorter lifespan than that of WT controls. Elimination of senescent cells from old Prf1-/- mice can be achieved by pharmacological inhibitors of the BCL-2 family of proteins, such as ABT-737. This pharmacological approach attenuates age-related phenotypes and gene expression profile in Prf1-/- mice.