Cellular senescence in aging and age-related disease: from mechanisms to therapy

Abstract

Cellular senescence, a process that imposes permanent proliferative arrest on cells in response to various stressors, has emerged as a potentially important contributor to aging and age-related disease, and it is an attractive target for therapeutic exploitation. A wealth of information about senescence in cultured cells has been acquired over the past half century; however, senescence in living organisms is poorly understood, largely because of technical limitations relating to the identification and characterization of senescent cells in tissues and organs. Furthermore, newly recognized beneficial signaling functions of senescence suggest that indiscriminately targeting senescent cells or modulating their secretome for anti-aging therapy may have negative consequences. Here we discuss current progress and challenges in understanding the stressors that induce senescence in vivo, the cell types that are prone to senesce, and the autocrine and paracrine properties of senescent cells in the contexts of aging and age-related diseases as well as disease therapy.

Figure 1

Effector pathways of three senescent cell types. Stresses inducing senescence vary depending on the in vivo context, although there is substantial overlap in processing of the stress-response signal and activating effectors of senescence. For example, in all reported cases, rising levels of cyclin-dependent kinase inhibitors drive entry into senescence by activating RB to block cell cycle progression. In embryonic senescence, elevated TGFβ and reduced PTEN activity upregulate SMAD-FOXO transcriptional activation of the cyclin-dependent kinase inhibitor p21, as well as activation of p15^Ink4b through unclear means. In contrast, acute senescence—in the placenta, after wounding or in response to oncogene activation or loss of the tumor suppressor PTEN—triggers DNA damage or p53 signaling to induce p21 and p16^Ink4a. Both embryonic and acute senescence are beneficial, and presumably these cells are cleared rapidly by the immune system as part of their program. These two settings contrast with chronic senescence, which is a response to the slowly accumulating macromolecular damage of age, such as telomere erosion, proteotoxicity, DNA damage and likely many others. Effectors of chronic senescence probably include p21 and p16^Ink4a, which are induced in aged tissues. Chronic senescence can also evolve from acute senescence if immune clearance is impaired with age, leading to prolonged arrest and possibly alterations in the SASP. In all senescence cases, cyclin-dependent kinase–mediated licensing of RB activity leads to an early senescent state where the arrest is permanent in vivo, but can be reversed with manipulation of single factors, such as p38 inhibition or inactivation of p16^Ink4a. These early senescent cells are SA-β-GAL positive and may not have a SASP. Senescent cells may evolve further into a truly irreversible full senescence with SA-β-GAL positivity and a SASP. The cellular changes driving this phenotypic switch in vivo are unclear but are likely to include robust processes such as heterochomatinization of cell cycle genes and activation of an NF-κB–dependent transcriptional program generating the SASP.

Figure 2

Senescence in aging, age-related diseases and disease-related treatments. (a) Common cellular stresses yield senescent cells that accumulate in various tissues over time and may contribute to tissue dysfunction even within healthy aging. (b,c) In contrast, disease-related senescence (b) and therapy-induced senescence (c) generate an additional burden of senescent cells on top of the chronic senescence generated by aging itself. An example of disease-related senescence is chronic obstructive pulmonary disease (COPD) following cigarette smoking, an addiction that causes DNA damage from compounds present in cigarette smoke as well as telomere shortening due to increased demand for repair placed on the injured airway epithelium. Both DNA damage and telomere shortening occur during normal aging, but in smoking, the duration and intensity of the stress is much higher. In this case, although there are peripheral effects of smoking, much of the damage is concentrated in the lung, and a majority of smoking-induced senescent cells probably occur there. Therefore, disease-related senescence occurs at a high rate in one or a few target organs and may drive aging with chronic disease. Therapy-induced senescence is the result of stressors due to medical intervention and can be both a desired outcome of therapy or an undesirable side effect. Here we focus on two examples of undesirable therapy-induced senescence. Chemotherapy is known to cause accelerated aging. One way in which this is thought to occur is through organism-wide telomere erosion and DNA damage in non-neoplastic cells, leading to systemically high levels of senescence. Therapy-induced senescence can also be promoted in solitary organs, such as the kidney in the case of kidney transplant. Here, ischemia-reperfusion drives oxidative damage, DNA damage and proteotoxicity, and attempts by the donor kidney to replace lost cells following engraftment leads to telomere erosion. These stresses cause a high, organ-specific senescence burden, potentially leading to graft rejection or diminished excretory function.

Figure 3

Senescent cells as drivers and amplifiers of disease. The interrelationship of senescence-driven tissue dysfunction, susceptibility to disease-causing stress and senescence in disease is illustrated by the example of type 2 diabetes mellitus (T2DM). In young adulthood (shown at left), fat exposed to a healthy diet is insulin responsive and receives sufficient levels of insulin from the pancreas to take up glucose, maintaining normoglycemia. Chronic, high levels of free fatty acids in the circulation, due to obesity and a high-fat diet, can drive insulin resistance in peripheral adipose tissue by inducing proinflammatory senescent cells in fat. The pancreas can initially meet the increased demand for insulin through proliferation of insulin-producing β cells, maintaining normoglycemia with hyperinsulinemia. However, following telomere erosion, the capacity of β cells to expand production of insulin is limited by senescence. If insulin resistance worsens further, hyperglycemia and T2DM develop with accumulation of additional senescent cells in the fat. In contrast to T2DM development in youth, in advanced age (right), a form of peripheral insulin resistance already exists in the absence of overt dietary stresses that is due in part to the accumulation of senescent cells in aged fat. Therefore, the aged pancreas and fat can develop T2DM when stressed with a high-fat diet that is quite mild when compared to what is required for pathology to develop in youth.

Figure 4

Senotherapies to prevent disease and extend healthy life span. Outright killing of senescent cells by reprogrammed cytotoxic T cells, antibodies against abundant (selective) surface proteins of senescent cells, or small-molecule inhibitors (senolyic or senoptotic molecules) of, for instance, pro-survival pathways that senescent cells engage to avoid apoptosis. Alternatively, blocking p38 MAPK or IL-1α could inhibit the SASP itself, though this strategy would require continuous treatment and may therefore disrupt beneficial functions of senescence or other inflammatory processes. Inhibiting purely deleterious SASP factors or senescence-specific exocytosis processes, if they exist, would sidestep this problem. Finally, preventing the stresses leading to senescence, but not the senescence program itself, may promote healthy aging and prevent disease. Preventative steps include healthy diet, exercise and avoidance of lifestyle stresses such as smoking, but may also include ‘anti-aging’ drugs such as metformin and rapamycin.