The Challenges of Cellular Senescence
HUMAN CELL
Classically, a senescent cell--one that no longer divides-- will have resulted when a stem cell had undergone multiple cell divisions, which events are generally accompanied by the shortening of the telomere, a biological clock marker of cellular aging. Cellular senescence is a physiologically irreversible growth arrest process that occurs when division-prone(-competent) cells encounter oncogenic stress.
In replicative senescence, the gradual loss of DNA at the end of the chromosome(the telomere), by DNA polymerases initialing RNA rather than DNA prime strand during replication and the lack of telomerases in most cells to effect repair, generate persistent DNA damage response (DDR), a vain attempt to repair DNA damage. This necessarily calls for cell division arrest.
Premature senescence occurs following damage to the DNA by oxidative stress, endoplastic reticulum stress that prompts autophagy and heat shock response; through inflammation, toxins, infections, from DNA breaks that evoke DDR. Nutritional stress and other hyperphysiological states can also induce senescence. Histone deacetylase inhibitors(including short chain fatty acids), relax chromatin and cause senescence(e.g. in fasting).
Cell division is arrested by P53, and if apoptosis is not initiated, because damage is less profound, heat shock protein is activated or P53 levels are low, senescence pathway is activated to check malignancy. Mitotic deficiency, in the case of senescence, occurs when some DNA replication will have taken place. There is polyploidy and multi-nuclei giant cells are born. They may be reactivated later, this time into cancer cells, if P53 protection is lost, due to genetic instability.
Senescent cells, commonly called zombie cells, are semi-dormant and have a secretory phenotype, with heightened genetic expression of metalloproteases, mucin, and cytokines, in fibroblasts and keratinocytes, hence highly inflammatory. They have inclusion bodies which are essentially amyloid from folding mishaps. Mitochondria are poor, showing substantial fission. Fat storage is promoted due to dysfunctional Kreb's cycle and electron transport chain proteins, more susceptible to oxidation and hyrolysis, with the mitochondrial membrane becoming less viable. Low levels of ATP are produced and more reactive oxygen species are generated.
Senescent cells are not quite quiescent or differentiated. These cells are flat, express more adhesion molecules and attach to the extracellular matrix with high avidity.
BACTERIA
In bacteria, senescence occurs after the motile phenotype, the plantonic form, finds food, feeds and multiplies rapidly. A small number only, becomes senescent initially. With metabolic stress, exhaustion and inclusion bodies formed; once, in response, heat shock protein expression is prompted, survival is promoted and this keeps apoptosis in check. At steadystate and beyond, apoptosis takes its toll from the overwhelming burden of toxic inclusion bodies, oxidative and nutritional stress. Senescent cells are semi-dormant and account for persisters.
Senescent persistent bacteria are found both intracellularly(in the host) and extracellularly and predate biofilm formation. If they die, they constitue and cause the maturation of biofilm, this without affecting the metabolic state, within biofilm, of normal cells--the ones that will normally respond to antibiotics. Biofilm induces senescence in human cells.
Both in the human stem cell and bacteria, senescence is governed by genetic and epigenetic factors.
DISEASE STATE AND HEALTH
Aging, chronic diseases such as diabetes, Alzheimer's, Parkinson's, arthritis and many other autoimmune diseases have as origin senescence. Senescence leads to amyloids which, in turn, as a toxin, cause senescence. Just like deregulated inflammation, senescence is self-propagating, and what starts as an innocuous small number of cells that can be easily handled by the immune system, eventually gets out of hand. Keratinocyes, melanocytes, fibroblasts, neurones, in fact, every stem cell, with perhaps the embryonic stem cell being the only exception, can senesce.
Subsequent, further damage that compromises stress response chaperones and their regulators, such as excessive autophagy, may push senescent cells into apoptosis, necroptosis or even necrosis. Senescent fibroblasts are more difficult to kill. Anything that increases metabolism and causes further damage, reactive oxygen species formation, such as intense exercise, high levels of vitamins D and A, TNF, calcium that activates kinases, fasting and will concomitantly enhance autophagy, will kill senescent cells through apoptosis and the hitherto overwhelmed immune cells will then cope, clearing these cells.
Of interest is the fact that having good normal flora in the gut and taking fiber will raise the levels of short chain fatty acids that accumulate and kill senescent cells. Exercise, apart from producing ketone bodies, in its own right, also produces nitric oxide that promotes the colonization, by aerobic normal flora, of the gut.
Substances such as quercetin, fisetin are currently being considered for killing problematic senescent cells(senolytics).
Dr. Oliver Verbe Birnso, MD
Classically, a senescent cell--one that no longer divides-- will have resulted when a stem cell had undergone multiple cell divisions, which events are generally accompanied by the shortening of the telomere, a biological clock marker of cellular aging. Cellular senescence is a physiologically irreversible growth arrest process that occurs when division-prone(-competent) cells encounter oncogenic stress.
In replicative senescence, the gradual loss of DNA at the end of the chromosome(the telomere), by DNA polymerases initialing RNA rather than DNA prime strand during replication and the lack of telomerases in most cells to effect repair, generate persistent DNA damage response (DDR), a vain attempt to repair DNA damage. This necessarily calls for cell division arrest.
Premature senescence occurs following damage to the DNA by oxidative stress, endoplastic reticulum stress that prompts autophagy and heat shock response; through inflammation, toxins, infections, from DNA breaks that evoke DDR. Nutritional stress and other hyperphysiological states can also induce senescence. Histone deacetylase inhibitors(including short chain fatty acids), relax chromatin and cause senescence(e.g. in fasting).
Cell division is arrested by P53, and if apoptosis is not initiated, because damage is less profound, heat shock protein is activated or P53 levels are low, senescence pathway is activated to check malignancy. Mitotic deficiency, in the case of senescence, occurs when some DNA replication will have taken place. There is polyploidy and multi-nuclei giant cells are born. They may be reactivated later, this time into cancer cells, if P53 protection is lost, due to genetic instability.
Senescent cells, commonly called zombie cells, are semi-dormant and have a secretory phenotype, with heightened genetic expression of metalloproteases, mucin, and cytokines, in fibroblasts and keratinocytes, hence highly inflammatory. They have inclusion bodies which are essentially amyloid from folding mishaps. Mitochondria are poor, showing substantial fission. Fat storage is promoted due to dysfunctional Kreb's cycle and electron transport chain proteins, more susceptible to oxidation and hyrolysis, with the mitochondrial membrane becoming less viable. Low levels of ATP are produced and more reactive oxygen species are generated.
Senescent cells are not quite quiescent or differentiated. These cells are flat, express more adhesion molecules and attach to the extracellular matrix with high avidity.
BACTERIA
In bacteria, senescence occurs after the motile phenotype, the plantonic form, finds food, feeds and multiplies rapidly. A small number only, becomes senescent initially. With metabolic stress, exhaustion and inclusion bodies formed; once, in response, heat shock protein expression is prompted, survival is promoted and this keeps apoptosis in check. At steadystate and beyond, apoptosis takes its toll from the overwhelming burden of toxic inclusion bodies, oxidative and nutritional stress. Senescent cells are semi-dormant and account for persisters.
Senescent persistent bacteria are found both intracellularly(in the host) and extracellularly and predate biofilm formation. If they die, they constitue and cause the maturation of biofilm, this without affecting the metabolic state, within biofilm, of normal cells--the ones that will normally respond to antibiotics. Biofilm induces senescence in human cells.
Both in the human stem cell and bacteria, senescence is governed by genetic and epigenetic factors.
DISEASE STATE AND HEALTH
Aging, chronic diseases such as diabetes, Alzheimer's, Parkinson's, arthritis and many other autoimmune diseases have as origin senescence. Senescence leads to amyloids which, in turn, as a toxin, cause senescence. Just like deregulated inflammation, senescence is self-propagating, and what starts as an innocuous small number of cells that can be easily handled by the immune system, eventually gets out of hand. Keratinocyes, melanocytes, fibroblasts, neurones, in fact, every stem cell, with perhaps the embryonic stem cell being the only exception, can senesce.
Subsequent, further damage that compromises stress response chaperones and their regulators, such as excessive autophagy, may push senescent cells into apoptosis, necroptosis or even necrosis. Senescent fibroblasts are more difficult to kill. Anything that increases metabolism and causes further damage, reactive oxygen species formation, such as intense exercise, high levels of vitamins D and A, TNF, calcium that activates kinases, fasting and will concomitantly enhance autophagy, will kill senescent cells through apoptosis and the hitherto overwhelmed immune cells will then cope, clearing these cells.
Of interest is the fact that having good normal flora in the gut and taking fiber will raise the levels of short chain fatty acids that accumulate and kill senescent cells. Exercise, apart from producing ketone bodies, in its own right, also produces nitric oxide that promotes the colonization, by aerobic normal flora, of the gut.
Substances such as quercetin, fisetin are currently being considered for killing problematic senescent cells(senolytics).
Dr. Oliver Verbe Birnso, MD
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