Epigenetic clock analysis of cellular senescence

According to a molecular biomarker of aging known as epigenetic clock,[14] the three major types of cellular senescence, namely replicative senescence, oncogene-induced senescence and DNA damage-induced senescence are distinct because induction of replicative senescence (RS) and oncogene-induced senescence (OIS) were found to be accompanied by epigenetic aging of primary cells but senescence induced by DNA damage was not, even though RS and OIS activate the cellular DNA damage response pathway.[15] These results highlight the independence of cellular senescence from epigenetic aging. Consistent with this, telomerase-immortalised cells continued to age (according to the epigenetic clock) without having been treated with any senescence inducers or DNA-damaging agents, re-affirming the independence of the process of epigenetic ageing from telomeres, cellular senescence, and the DNA damage response pathway.

Although the uncoupling of senescence from cellular aging appears at first sight to be inconsistent with the fact that senescent cells contribute to the physical manifestation of organism ageing, as demonstrated by Baker et al., where removal of senescent cells slowed down aging .[10] However, the epigenetic clock analysis of senescence suggests that cellular senescence is a state that cells are forced into as a result of external pressures such as DNA damage, ectopic oncogene expression and exhaustive proliferation of cells to replenish those eliminated by external/environmental factors.[15] These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues, which is interpreted as organism ageing. However, at the cellular level, aging, as measured by the epigenetic clock, is distinct from senescence. It is an intrinsic mechanism that exists from the birth of the cell and continues. This implies that if cells are not shunted into senescence by the external pressures described above, they would still continue to age. This is consistent with the fact that mice with naturally long telomeres still age and eventually die even though their telomere lengths are far longer than the critical limit, and they age prematurely when their telomeres are forcibly shortened, due to replicative senescence. Hence senescence is a route by which cells exit prematurely from the natural course of cellular ageing.[15]

Aging of the whole organism

Organismal senescence is the aging of whole organisms. In general, aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate consequence of aging, though “old age” is not a scientifically recognized cause of death because there is always a specific proximal cause, such as cancer, heart disease, or liver failure. Aging of whole organisms is therefore a complex process that can be defined as “a progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability.”[16]

Differences in maximum life span among species correspond to different “rates of aging.” For example, inherited differences in the rate of aging make a mouse elderly at 3 years and a human elderly at 80 years.[17] These genetic differences affect a variety of physiological processes, including the efficiency of DNA repair, antioxidant enzymes, and rates of free radicalproduction.

Supercentenarian Ann Pouder(8 April 1807 – 10 July 1917) photographed on her 110th birthday. A heavily lined face is common in human senescence.

Senescence of the organism gives rise to the Gompertz–Makeham law of mortality, which says that mortality rate accelerates rapidly with age.

Some animals, such as some reptiles and fish, age slowly (negligible senescence) and exhibit very long lifespans. Some even exhibit “negative senescence”, in which mortality falls with age, in disagreement with the Gompertz–Makeham “law”.[1]

Whether replicative senescence (Hayflick limit) plays a causative role in organismal aging is at present an active area of investigation.

The oft-quoted evolutionary theorist George Williams wrote, “It is remarkable that after a seemingly miraculous feat of morphogenesis, a complex metazoan should be unable to perform the much simpler task of merely maintaining what is already formed.”[18]

There is a current debate as to whether or not the pursuit of longevity and the postponement of senescence are cost-effective health care goals given finite health care resources. Because of the accumulated infirmities of old age, bioethicist Ezekiel Emanuel, opines that the pursuit of longevity via the compression of morbidity hypothesis is a “fantasy” and that human life is not worth living after age 75; longevity then should not be a goal of health care policy.[19]

This opinion has been refuted by neurosurgeon and medical ethicist Miguel Faria, who states that life can be worthwhile during old age, and that longevity should be pursued in association with the attainment of quality of life.[20] Faria claims that postponement of senescence as well as happiness and wisdom can be attained in old age in a large proportion of those who lead healthy lifestyles and remain intellectually active.

Cellular senescence

As noted above, senescence is not universal. It was once thought that senescence did not occur in single-celled organisms that reproduce through the process of cellular mitosis.[36] Recent investigation has unveiled a more complex picture. Single cells do accumulate age-related damage. On mitosis the debris is not evenly divided between the new cells. Instead it passes to one of the cells leaving the other cell pristine. With successive generations the cell population becomes a mosaic of cells with half ageless and the rest with varying degrees of senescence.[37]

Moreover, cellular senescence is not observed in several organisms, including perennial plants, sponges, corals, and lobsters. In those species where cellular senescence is observed, cells eventually become post-mitotic when they can no longer replicate themselves through the process of cellular mitosis; i.e., cells experience replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but (as noted above) it is sometimes suggested that cellular senescence evolved as a way to prevent the onset and spread of cancer. Somatic cells that have divided many times will have accumulated DNA mutations and would therefore be in danger of becoming cancerous if cell division continued. As such, it is becoming apparent that senescent cells undergo conversion to an immunogenic phenotype that enables them to be eliminated by the immune system.[38]

Lately, the role of telomeres in cellular senescence has aroused general interest, especially with a view to the possible genetically adverse effects of cloning. The successive shortening of the chromosomal telomeres with each cell cycle is also believed to limit the number of divisions of the cell, thus contributing to aging. There have, on the other hand, also been reports that cloning could alter the shortening of telomeres.

Some cells do not age and are, therefore, described as being “biologically immortal“. It is theorized by some that when it is discovered exactly what allows these cells, whether it be the result of telomere lengthening or not, to divide without limit that it will be possible to genetically alter other cells to have the same capability.

It is further theorized that it will eventually be possible to genetically engineer all cells in the human body to have this capability by employing gene therapy and, therefore, stop or reverse aging, effectively making the entire organism potentially immortal.

The length of the telomere strand has senescent effects; telomere shortening activates extensive alterations in alternative RNA splicing that produce senescent toxins such as progerin, which degrades the tissue and makes it more prone to failure.[39]

Cancer cells are usually immortal

In about 85% of tumors, this evasion of cellular senescence is the result of up-activation of their telomerase genes.[40] This simple observation suggests that reactivation of telomerase in healthy individuals could greatly increase their cancer risk.

Ned Sharpless and collaborators demonstrated the first in vivo link between p16-expressing senescent cells and lifespan.[41]They found delayed senescent cell accumulation in mice with mutations that extend lifespan, as well as in mice that had their lifespan extended by food restriction. Later, Jan van Deursen and Darren Baker in collaboration with Andre Terzic at the Mayo Clinic in Rochester, Minn., provided the first in vivo evidence for a causal link between cellular senescence and aging by preventing the accumulation of senescent cells in BubR1 progeroid mice.[42]

In the absence of senescent cells, the mice’s tissues showed a major improvement in the usual burden of age-related disorders.

They did not develop cataracts, avoided the usual wasting of muscle with age. They retained the fat layers in the skin that usually thin out with age and, in people, cause wrinkling. Jan van Deursen, James Kirkland, Tamara Tchkonia, Nathan LeBrasseur, and Darren Baker at the Mayo Clinic in Rochester, Minn., provided the first direct in vivo evidence that cellular senescence causes signs of aging by eliminating senescent cells from progeroid mice by introducing a drug-inducible suicide gene and then treating the mice with the drug to kill senescent cells selectively, as opposed to decreasing whole body p16.[10] Another Mayo study led by James Kirkland in collaboration with Scripps and other groups demonstrated that senolytics, drugs that target senescent cells, enhance cardiac function and improve vascular reactivity in old mice, alleviate gait disturbance caused by radiation in mice, and delay frailty, neurological dysfunction, and osteoporosis in progeroid mice.

Discovery of senolytic drugs was based on a hypothesis-driven approach: the investigators leveraged the observation that senescent cells are resistant to apoptosis to discover that pro-survival pathways are up-regulated in these cells. They demonstrated that these survival pathways are the “Achilles heel” of senescent cells using RNA interference approaches, including Bcl-2-, AKT-, p21-, and tyrosine kinase-related pathways. They then used drugs known to target the identified pathways and showed these drugs kill senescent cells by apoptosis in culture and decrease senescent cell burden in multiple tissues in vivo.

Importantly, these drugs had long term effects after a single dose, consistent with removal of senescent cells, rather than a temporary effect requiring continued presence of the drugs. This was the first study to show that clearing senescent cells enhances function in chronologically aged mice.

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