Cellular senescence is important in aging. Cells can become senescent in response to damage, a toxic environment, or reaching the Hayflick limit on replication. Senescent cells undergo profound changes to architecture and protein expression that halt replication, cause a growth in size, and produce a potent mix of growth factors and inflammatory signals. Over the short term, this is useful. Senescent cells aid in wound healing and cancer suppression, provided that they are soon destroyed, either by programmed cell death or the immune system. With advancing age, however, senescent cells accumulate in tissues. There is too much creation, while mechanisms of clearance become slow and erratic. The secretions of senescent cells cause chronic inflammation and tissue dysfunction when present over the long term: this is a contributing cause of aging and age-related disease.
Numerous research groups and biotech companies are involved in developing a range of senolytic therapies capable of selectively destroying senescent cells. This is a still comparatively new, but very important branch of medicine. Clearance of senescent cells is literally a rejuvenation therapy, as these errant cells are in effect actively maintaining a degraded state of tissue function. Remove them, and a portion of aging is removed. Numerous age-related conditions have been meaningfully reversed in animal studies of senolytic therapies, including surprising structural reversals such as ventricular hypertrophy.
The promise of this new field of medicine ensures that a great deal of effort is now devoted to mapping the fundamental biochemistry of senescent cells. Scientists are in search of ways to sabotage the survival mechanisms of senescent cells, or their damaging secretions. In that vein, today’s open access paper is a review of what is known of the extensive genomic reorganization exhibited by senescent cells. It is almost certainly the case that somewhere in there are novel mechanisms of selective cell destruction that will be discovered and developed for clinical use in the years ahead.
Aging is a physiological condition characterized by the functional deficit of tissues and organs due to the accumulation of senescent cells. The key role of senescence in aging is well-established. Clearance of senescent cells in mouse models delays the appearance of age-related tissue and organ diysfunctions. Senescent cells are characterized by the permanent cell-cycle arrest sustained by the accumulation of cyclin-dependent kinase inhibitors (CDKi), like p16, p21, and p27, as well as by the release of cytokines, chemokines, and soluble factors. This modified microenvironment is known as senescence-associated secretory phenotype (SASP). The senescence state is triggered by different stimuli/stressors. These include the shortening of the telomeres (replicative senescence), the oncogene-induced replication stress, the oncogene-induced senescence (OIS), the accumulation of misfolded protein and/or oxidative stress (stress-induced premature senescence, SIPS).
The impairment of the non-homologous end joining (NHEJ) and homologous recombination (HR) repair mechanisms are common traits of senescent cells. Moreover, a widespread epigenetic resetting characterizes senescent cells and sustains cell-cycle arrest and cellular survival, through the activation of (i) CDKi, (ii) tumor suppressors, and (iii) secretion of chemokines and cytokines, as well as the remodeling of the microenvironment.
Macroscopically, senescent cells are characterized by the formation of peculiar areas of heterochromatin, named as SAHF (senescence-associated heterochromatin foci), mainly at E2F loci. However, SAHF do not characterize all senescent cells and are not causally linked to the onset of senescence. Other epigenetic features, like the distension of satellites (senescence-associated distension of satellites, SADS), the re-activation of transposable elements, and of endogenous retroviruses (ERV), seem to better qualify different types of senescence. Finally, aging appears to be marked by substantial re-arrangements of the nucleosomes, with the loss of histones H3 and H4. During senescence the epigenome undergoes temporal and sequential modifications that are mandatory to accomplish different cellular adaptations. Initially, this epigenetic resetting is mainly due to the accumulation of irreparable DNA damage. After this first wave of epigenetic modifications, the epigenome is remodeled and fixed in order to sustain the permanent cell-cycle arrest and to modulate the microenvironment.
The accumulation of double strand breaks (DSBs) in DNA is a general hallmark of senescence and aging. The main endogenous sources of DSBs are telomere attrition and replicative stress. Replication stress is commonly observed in RS, OIS and aging. In all these conditions cells slow down DNA synthesis and replication fork progression. However, the reduced replication fork speed activates dormant origin to preserve replication timing during replication stress. This adaptive response allows the maintenance of an unaltered replication timing also in cells entering senescence. On the other side it exposes common fragile sites (CFSs), which are genomic loci more prone to breakage after DNA polymerase inhibition, and the accumulation of genomic alterations. CFS alterations are typically observed in pre-neoplastic lesions. Similarly, cells exposed to genotoxic agents (e.g., chemotherapeutic agents, pollutants, and toxins) or to oxidative stress activate the DDR that frequently leads to cell-cycle arrest. Whatever the origin, the accumulation of irreparable DNA damage gives rise to a response characterized by the activation of tumor suppressors and CDKi and by the release of pro-inflammatory cytokines.
Global histone loss, as well as the focused deposition of histone variants (H2AX, H2AZ, H2AJ, H3.3 and macroH2A) and the redistribution of H3K4me3, H3K27me3, and H3K36me3 characterize both DNA damage response, DSBs, and senescence. The chromatin remodeling observed in different senescence models seems to represent a temporal and spatial evolution of what is observed after a short-time treatment of the cells with DNA damaging agents. Cancer cells appear as forgetful cells that have lost the epigenetic memory of a healthy genome. Aging seems to be predisposed to this memory loss. One of the major challenges of the future, regarding the treatment of aging and cancer, will be the identification of the framework of epigenetic changes that can restore this memory.