Senescent cell accumulation is an important cause of degenerative aging. Senescent cells cease replication and begin to secrete an inflammatory mix of signals that disrupt tissue structure and function. These cells are created constantly, largely as a result of somatic cells hitting the Hayflick limit on cellular replication, but also as a result of injury, molecular damage, inflammation, and the like.
Near all senescent cells are rapidly destroyed, either via programmed cell death mechanisms, or via the immune system. This clearance falters with age, however, slowing down, becoming less efficient, and allowing senescent cells to accumulate, disrupt tissue function, and provoke chronic inflammation.
The targeted destruction of senescent cells has been shown – in animal models – to reverse the progression of many age-related conditions and extend healthy life span. It is easy to demonstrate such results, and many research groups have used many different methods to destroy senescent cells. To the extent that these errant cells are removed, benefits follow. As these demonstrations have accumulated over the years, researchers have broadened their investigations of the biochemistry of senescent cells.
One class of outcome of this work is represented by today's open access paper. Researchers have identified a gene that affects the burden of cellular senescence, and find that adjusting expression levels down or up also adjusts lifespan as well, due to there being greater or lesser numbers of senescent cells present in older individuals.
This is a good secondary demonstration of the importance of senescent cells to aging and longevity, but not really a good basis for building interventions. Senolytic therapies that destroy senescent cells are just too good a class of treatment to see much competition from this front.
In the case of senolytics: large beneficial effects are achieved very quickly; treatment is only needed intermittently, such as once every few months at most; the first generation drugs cost very little. That compares very favorably with a senescence suppression treatment that would have to be taken continuously across a lifetime, with only small benefits in the short term, particularly given that senescent cells are actually beneficial for wound healing and cancer suppression when present in small numbers, and briefly.
Aging is characterized by a functional decline across multiple organ systems and is a risk factor for many human diseases. Substantial evidence has demonstrated that senescence is a key hallmark of the aging process and plays a critical roles in controlling aging and aging-associated diseases. Senescence is a cellular response that acts to restrict the proliferation of aged and damaged cells, and is also a state of growth arrest and pro-inflammatory cytokine release in response to stresses. One hallmark of cellular senescence is the secretion of excessive proinflammatory cytokines, chemokines, extracellular matrix proteins, growth factors, and proteases termed the senescence-associated secretory phenotype (SASP). Senescence constitutes a stress response triggered by insults associated with aging including genomic instability and telomere attrition.
DNA damage is a causal factor in the aging process that drives cells into senescence or apoptosis as results of the DNA damage response (DDR) controlled by DNA repair processes. DNA double-strand break (DSB) repair is known to decline age, leading to the accumulation of genomic rearrangements. Mutations in DNA DSB repair genes reduce lifespan, indicating that DNA repair pathways play a critical roles in the aging process.
The Myb-like, SWIRM, and MPN domains-containing protein 1 (MYSM1) is a histone 2A (H2A) deubiquitinase that specifically deubiquitinates H2A. It is a key functional regulator of hematopoietic stem cells, lymphocytes, and blood cells, and serves as an important regulator of tissue differentiation. MYSM1 is also linked to heritable bone marrow failure syndromes, plays a role in regulating skin development in mice, and impedes antiviral signaling. Loss of Mysm1 has been shown to promote activation of the p53 stress response and induced abnormal cell development and tissue differentiation. More recently, a study revealed that Mysm1 levels increase in response to etoposide-induced DNA damage and that mice lacking Mysm1 show a shorter lifespan. These important roles of MYSM1 implicate that it may be involved in the regulation of cellular senescence and the aging process.
The present study showed that MYSM1 is a key suppressor of senescence and aging. Functionally, MYSM1 functionally represses DDR-associated SASP and the aging process. Mechanistically, MYSM1 represses the aging process by promoting homologous recombination (HR) mediated DNA repair. Mysm1 deficiency promotes aging and aging-related pathologies and reduces lifespan in mice. AAV9-Mysm1 was shown to attenuate the aging process to prolong the lifespan of mice. Our data suggest that Mysm1 is a potential agent for the prevention of aging and aging-related diseases.
Source: Fight Aging!