Aging kills by age-related disease. Aging and age related disease are merely different manifestations of the same disease process. If not for aging; there would not be age-related disease.
At the center of Aging is elevated mTOR and senescent cells.
The purpose of this new website is to provide an in depth examination of the part played by senescent cells in Aging and age-related disease. The website also undertakes a detailed examination of senolytics, which are drugs which remove senescent cells.
There is now a sufficient body of evidence to justify the introduction of SENOLYTICS into clinical medicine.
COVID-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. Mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. At its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. The hyperfunction theory of quasi-programmed aging explains why COVID-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. It also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with COVID-19 vulnerability. Anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing COVID-19 vulnerability.
A senescent cell is not just one bad cell. It is the rotten apple that slowly corrupts everything around it. Senescent cells produce SASP, a devils brew of poisons. Most SASP act locally and are called paracrine, hormones having a local effect. Some SASP can have a systemic effect. The local SASP effects are 2 fold:
a. The bad effects on local cells promoting disease.
b. Converting good cells into more senescent cells.
Also senescent cells do not do their primary job which was to divide and become two brand new healthy cells which can then help do the job of that organ.
Instead senescent cells stick around, refuse to die, become big trouble makers and corrupt good cells.
The very short story is senescent cells are like zombies. You have to kill them before they kill you.
The list of diseases in which senescent cells play a major role in pathogenesis is a very long list and may involve the great majority of chronic diseases.
The list starts with "A":
And on and on
Lewis-McDougall, Kirkland, 2019.
D+Q animal study.
"Like other organs, the adult mammalian hear has the capacity, albeit low, to self-renew cardiomyocytes over the human lifespan."
The self-renewing cells are called "multipotent cardiac stem cells" and progenitor cells" hereafter abbreviated CPCs. About 1% of heart cells are CPCs.
Cardiac aging and pathology affects the activity and potency of CPCs which translates into diminished capacity of the aging and diseased myocardium to repair and regenerate.
In the old and failing heart there is the accumulation of senescent CPCs. Senescent CPCs can't divide and have very diminished self-renewal, differentiation and regenerative potential. Furthermore, senescent CPCs have a SASP that negatively affects non-senescent cycling-competent CPCs, rendering them senescent.
This study is about effect of eliminating senescent CPCs and restoring capacity to remaining CPCs.
1. CPCs exhibit a senescent phenotype with increased age.
Fig 1: "Over half of CPCs in the aged human heart are senescent."
2. CPCs from old subjects show impaired cell growth and differentiation. Only about half of CPCs old myocardium are senescent. However, non-senescent indistinguishable from young subjects.
3. Aged-senescent CPCs lose their regenerative capacity in vivo.
4. Aged-senescent CPCs have a senescent associated secretory pheotype (SASP).
5. Elimination of senescent CPCs using senolytic drugs abrogates the SASP in vitro.
Study showed Dasatinib effectively cleared CPCs, whereas Fisetin was less effective.
6. Elimination of senescent cells in vivo activates resident CPCs and increases number of small, proliferating cardiomyocytes in the aged heart."
To determine effect:
D+Q treatment administered in 4 cycles for 3 consequtive days, 12 days apart, to 24-32 month mice.
D+Q increased numbers CPCs.
D+Q treated had small newly formed proliferating myocytes in contrast to non-treated controls only old hypertrophic cells.
D+Q mice had decrease in fibrosis in left ventricle.
No D+Q effect in young mice.
"These finding show that clearance of senescent cells leads to stimulation of CPCs and cardiomyocytes with increased DNA-synthesizing activity and that this strategy is specific to the aged heart."
"Our study shows that CPCs isolated from the failing human heart develop a senescent phenotype...Aged human hearts with dilated cardiomyopathy showed greater numbers of senescent cells.
Our finding demonstrate that CPCs accumulate in the failing hearts of elderly subject (>70 years) and are dysfunctional, compared to CPCs isolated from the hearts of middle-aged (32-66 years) subjects.
As the adult heart possesses very low numbers (<1%) of CPCs, furthermore by 80 years of age >50% of resident CPCs are senescent.
The presence of SASP in the aged and failing heart impairs the function of the remaining nonsenescent CPCs.
Study showed D+Q increased numbers of immature and newly formed myocytes.
The frequency of resident cardiac stem and progenitor cells in healthy myocardium including humans is approximately one per every 1000-2,000 myocytes depending on age. We detected a 23-foldi ncrease in the number of CPCs following elimination of senescent cells with D+Q. Moreover 10% of CPCs after elimination of senescent cells were activated young cells showing a 9 fold increase wit D+Q.
The number of DNA-synthesizing cardiomyocytes in young mous is 0.12% and in old 22 months old was 0.07% oftotal cardiomyocytes. Elimination of senescent cells led to triple the number in old hearts.
Therefore, the present data represent a significant and physiologically relevant increase in cardiomyocyte DNA synthetic activity following clearance of senescent cells. These finding are consistent with the hypothesis that clearing senescent cells can beneficially alter stem and progenitor cell function across multiple tissues.
"In conclusion, the present work demonstrates that eliminating senescent cells may be useful for treating age-related cardiac deterioration and rejuvenating the regenerative capacity of the aged heart."
"Aging leads to increased cellular senescence and is associated with decreased potency of tissue-specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32-86 years. In aged subjects (>70 years old), over half of CPCs are senescent and unble to replicate and restore cardiac function. SASP factors secreted by senescent CPCs render otherwise healthy CPCs to senescence. Elimination of senescnt CPCs using senolytics (D+Q) abrogates the SASP and its debilatative effects in vitro. Global elimination of senescent cells in aged mice using D+Q senolytics in vivoactivates resident CPCs and increased the numbers of new myocytes.
"Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenertive capacity of the heart."
This paper gives an extraordinary insight into the aging heart and aging in general. Putting aside specific cardiac disease such as ASHD, the heart must replace the work force of cardiomyocytes. CPCs form the new cells. If half the CPCs. don't work because they are senescent and these senescent cells render healthy CPCs senescent and non-functional, the heart will soon not have enough working cardiomyocytes and fail.
In medicine, this failure to rejuvenate new cells leading to organ failure is viewed as normal aging and not a disease. However, this paper shows that this process can be viewed as senescent cell disease; a treatable condition.
Childs, 2016, Mayo Clinic, Rochester, MN.
This is a classic paper, explaining exactly what we have been waiting for the past 100 years, the explanation of the pathogenesis of the number 1 killer of our times, atherosclerosis.
They used a very sophisticated transgenic and pharmacologic approach. They used an atherosclerosis-prone low-density lipoprotein receptor-deficient (Ldlr -/-) mouse which develops atherosclerosis on high fat diet. Into mice put a suicide gene which would kill senescent cells upon command; the command being administration of anti-viral drug, ganciclovir (GCV). This allowed them to study role of senescent cells in pathogenesis of atherosclerosis.
Starting at 10 weeks old, mice fed either a high fat diet or low fat diet for 88 days. Atherosclerotic plaque was present in aortic arch of mice on high fat diet; but not low fat diet. The atherosclerotic plaque contained senescent cells.
The senescent cells had SASP components including matrix metalloproteases (MMP) and inflammatory cytokines. There were 3 types of senescent cells, endothelial like cells, VSMCs (vasular smooth muscle cells, and lipid-loaded foamy macophages.
When treated 10 week old mice with GCV to remove senescent cells, the prooduction of plaque burden was reduced 60%.
At 9 days the first changes was fatty-streak with senescent foamy macrophages. The intimal senescent foamy macrophagesis are the first step and they produce proatherogenic factors. The subendothelial senescent foamy macrophages are monocytes recruited from the blood.
They next studied how early benign plaques develop into complex advanced lesions.
They continued with same mouse model. After 88 days on high fat diet; they continued for another 100 days on high fat diet.
The mice developed very advanced atherosclerotic lesions.
Elimination of senescent cells with GCV stopped progression of atherosclerosis.
(The usual suspect)
"Senescent cells promote plaque instability by elevating metalloprotease production."
Atherosclerotic clinical symptoms are associated with plaque rupture, clot formation and sudden obstruction. Matrix mettaloproteases (MMP) dissolves collagen and causes plaque destabilization. The mouse models show markers of plaque instability including fibrous cap thinning, decreased collagen deposition, elastic fiber degradation, and plaque calcification. These are all driven by senescent cells and ameliorated by removal of senescent cells.
"Advanced atherosclerotic lesions contain senescent cells.Using approaches to eliminate senescent cells we show thses senescent cells are detrimental throughout disease pathogenesis. "We find that foamy macrophages with senescent markers accumulate in the suubendothelial space at the onset of atherosclerosis, where they drive pathology by increasing key atherogenic and inflammatory cytokines and chemokines (attract other cells).
In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, byheightening mettaloprotease production.
"Together, these results demonstrate that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis."
"Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice". Roos. Kirkland, 2016, Mayo Clinic, Rochester, MN.
Study to determine whether long-term senolytic treatment with D+Q improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged and hypercholesterolemic mice with established disease.
Standard mice, fed on regular chow, 24 months old; were then initiated on D+Q once monthly for 3 months.
In the aorta, D+Q markedly reduced senescent cells in both endothelial and smooth muscle layer.
D+Q improved vascular relaxation in response to acetycholine. Interpretation was improved NO signaling.
D+Q also reduced medial vascular calcification in aorta and protein levels of osterix (early bone).
ApoE-/- mice were fed a Western atherogenic diet for 4 months to allow development of established atherosclerosis.
Mice then fed D+Q once weekly for next two months.
Senescent cells were present in media and intimal plaques of aorta from control mice.
In D+Q treated mice, senescent cells burden reduced in medial segments of vessels; but not from established intimal atherosclerotic plaques.
D+Q modestly improved vascular relaxation to acetycholine, markedly improved relaxation to sodium nitroprusside and had markers of improved NO signaling.
In accordance with no reduction in senescent cell burden in intimalplaque; there was no reduction in size of plaque or lipid composition.
There was significant reduction of intimal calcification by D+Q. No change in intimal plaque fibrosis.
Calcification and osterix (bone) in media was reduced.
The interpretation was there was limited plaque penetration by D+Q. However, significant reduction in plaque calcification was unusual as change in calcification very refractory to standard treatment.
"Collectively, this study shows that chronic pharmacological clearance of senescent cells alleviates vasomotor dysfunction in naturally aging mice and mice with established aherosclerosis. Furthermore, senescent cell clearance reduces markers ofosteogenesis in advanced intimal plaques, ultimately reducing intimal plaque calcification. Based on these finding, we conclude that senescent cell clearance may be an effective complemantary therapy to classical risk factor management to reduce morbidity and mortality with age-related cardiovascular disease."
Looking at these 3 papers together; long-term D+Q looks like an excellent addition to management of cardiovascular disease.
This is an extraordinary paper from Barshop Institute, San Antonio, Texas.
Neurofibrillary Tangles (NFT) which are insoluble Tau protein inclusions within neurons have been recognized for over 100 years as one of the cardinal features of Alzheimer's disease (AD).
"Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer's disease, progressive supranuclear palsy, traumatic brain injury and over 20 others. Tau-containing NFT accumulation is the closest correlate with cognitive decline and cell loss, yet mechanisms mediating tau toxicity are poorly understood."
NFT-containing neurons are long-lived and do not induce immediate cell death. NFT-containing neurons may survive decades. This 100 year old question is:
WHAT IS SO BAD ABOUT NFT ?
The answer is neurons containing NFT become senescent and act like ZOMBIE cells. The NFT-containing neurons destroy the brain. The hapless neuron which starts as the innocent victim, then becomes the mass murderer.
The simple solution is if neurons containing NFT are senescent cells acting like zombies; then just bring on the Zombie killers. In this study they did just that,
They used D+Q as the best characterized senolytic to determine the utility of targeting cellular senescence to treat tau-associated neurodegeneration in late life.
20 month old transgenic mice with advanced tau pathology were treated with D+Q at biweekly intervals for 3 months.
1. The number of NFT-containing neurons was reduced 35%
2. Brain atrophy is highly correlated with lateral ventricle enlargement. Ventricle size was reduced 28% indicating less atrophy. "The absence of full rescue of ventricular enlargement was not completely unexpected considering the severity of the disease and late age when treatment initiated."
3. DQ improved aberrant cerebral blood flow to a level not statistically different from controls. Aberrant cerebral blood flow is a functional defect closely associated with cognitive impairment.
1. NFT-bearing neurons from postmortem AD brain tissue display upregulated genes of senescent profile.
2. NFTs in tau transgenic mice show genetic profile of senescence.
3. NFTs were associated with evidence of DNA damage, SASP, NFkB and aberrant mitochondrial function characteristic of senescent cells.
4. A genetic approach showed a gene they characterized as Cdkn2a which is most highly characteristic of senescent cells was upregulated with NFT onset and correlated with NFT density.
5. Same gene upregulated with senescence was specific to NFT pathology and correlated to brain atrophy.
5. Same gene pattern correlated with NFT-containing brains from patients with progressive supranuclear palsy (a pure NFT tau disease in humans.)
"Using four AD transgenic mouse, we found that NFTs, but not AB plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP (progressive supranuclear palsy) to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these finding indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative disease, these finding have broad implications for understanding,and potentially treating, dozens of brain diseases."
This paper presents a revolutionary new way of looking at neurodegeneration in Tau diseases. It provides a way to prevent disease and a way to treat advanced disease.
"Senolytic therapy alleviates AB-associated oligodendrocytes progenitor cell senescence and cognitive deficits in an Alzheimer's disease model." Zhang, 2019.
Paper identifies an Oligodendrocyte progenitor glial cells that becomes senescent in presence of beta-amyloid deposits in AD. These cells then drive AD disease pathology. These destruction with D+Q ameliorates AD pathology and cognitive deficits.
The glial cells in the brain are the oligodendrocytes, astrocytes and microglia. The oligodrodrocytes arise from oligodendrocyte progenitor cells (OPCs). OPCs are a major population of cells in the brain which are mobilized in response to neuronal injury and demyelination and then proliferate into mature oligodrodrocytes to aid in repair. However, direct exposure of OPCs to beta-amyloid (AB) causes them to become senescent cells. Then their SASP profile drives AD.
7.5 month olf transgenetic mice were administer D+Q daily for 9 days. Short-term treatment removed the senescent OPC cells and reduced the proinflammatory cytokine activity and reduced microglia activation.
Long-term treatment was D+Q was administered once a week for 11 weeks beginning at 3.5 month old transgenic mice. At both 6 and 11 weeks the D+Q treated mice performed significantly better in the hippocampus-dependent learning and memory tests.
There was a significant reduction in the AB-plaque load, plaque size, proinflammatory cytokines and great reduction in senescent cells.
Cellular senescence has been most extensively studied in peripharal tissues, where cell turnover (proliferation,differentiation and cell death is robust. In such tissues, senescent cells accumulate during normal aging and their SASP contributes to age-related disease. In contrast to proliferative tissues, the major cell population in the brain are either postmitotic (neurons) or quiescent (astrocytes, oligodendrocytes and microglia). OPCs are the major proliferative cell in most brain regions. In response to ischemic and traumatic brain injuries, OPCs migrate into damage tissues where they can differentiate into oligodendrocytes and remyelinate damages axons.
The data here show that OPCs undergo senescence in the AB plaque environment and then contribute to local inflammation and damage to healthy neurons.
The finding suggest following steps:
1. Senescent cells that express OPC marker proteins are present in the AB plaque environment in the brins of patients with AD and the AD mouse model.
2. In AB plaques, OPCs become senescent with a proinflammatory phenotype.
3. Aggregating AB can act directly on OPCs to induce cellular senescence.
"Senolytic treatment of AD mice with D+Q selectively removed senescent cells from the plaque environment, reduced neuroinflammation, lessened AB load, and ameliorated cognitive deficits. Our finding suggest a role for AB-induced OPC cell senescence in neuroinflammation and cognitive deficits in AD, and a potential therapeutic benefit of senolytic treatments" with D+Q.
Cell senescence appears to be the missing link explaining the cascade of events in which AB accumulation causes accelerated cognitive impairment in AD.
When cells are exposed to an insult there generally may be one of three outcomes:
1. The cell recovers: Very good
2. The cell dies: Not good, but usually OK, unless death is massive.
3. The disease process results in chronic inflammation with production of senescent, zombie-like cells. The is worst outcome.
#3 Appears to be disease process behind PD.
The senescent cells are:
1. Senescent Astrocytes
2. Senescent Dopamine producing neuron in substantia nigra of midbrain.
Alpha- synuclein aggregates appear to act as middle-man between disease neurons and astrocytres spreading senescence and disease propagation
The finding that the dopamine neurons can become senescent is a very new finding published October 2019.Neurons are non-dividing long-lived cells so finding that dopamine neuron can become senescent is extraordinary and huge new insight into pathogenesis of PD.
The ground-breaking papers is from the prestigious Rockefeller University entitled:
"Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons." Riessland, 2019.
ScienceDaily had the subdued headline "The pathway to Parkinson's takes a surprising twist."
Parkinson's News Today had provacative headline "Targeting Dopaminergic Neurons in 'Zombie' state might slow Parkinson's progression, Study Says,"
At the heart of Parkinson's disease is loss of function of substatia nigra dopamineric neurons result in loss of dopamine and motor sysmptoms. The study shows these key neurons are senescent and not dead.
The key finding was loss of substance called SATB1 results in high expresiion of p-21 which induces senescence in dopamine producing neurons. Senescence is common in diviiding cells; but senescence in neurons, a post-mitotic cells, was a very unusual finding. Senescence may be unique to dopaminergic neurons. Loss of SATB1 did not cause senescence in cortical neurons.
The senescent neurons secreted inflammatory factors which cause harm to neighboring neurons and promote inflammation.
The critical mediator was control of p-21 and this determines senescence or not senescence.
Summary: "We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 auses activation of a cellular senescence transcriptional program in dopaminergic neurons both in human stem cell-derived dopaminergic neurons and in mice. ..Moreover, we found that SATB1 directly represses expresson of the pro-senescence factor p21 in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor in the pathology of Parkinson's disease."
Discussion: "There have been a number of studie that revealed phenotypes in PD brains that could be attributed to cellular senescence (examples)...However, none of the above mentioned studies have connected these finding to neuronal senescence."
Ogrodnik, Kirkland, 2019.
D+Q senolytic study
Obesity drives senescence in glial cells in Lateral ventricles of mouse brain.
Senescent cells Impair Neurogenesis and drives Anxiety.
Clearance of senescent cells with D+Q restores neurogenesis and ameliorates anxiety.
"Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate role of senescent cells we used D+Q to eliminate senescent cells. We found that obesity results in the accumulation of senescent cells in proximity to the lateral ventricles, a region in which adult neurogenesis occurs...Clearing senescent cells in obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics (D+Q) are a potential new therapeutic avenue for treating neuropsychiatric disorders."
1. Obese Mice show Increased Anxiety-like Behavior Not related to Body Mass.
2. Clearance of Senescent Cells with D+Q Alleviates Obesity related Behavioral Changes.
3. Clearance senescent Cells with D+Q reduces Circulating Cytokine levels
4. Senolytic Treatment with D+Q Reduces Senescent cells in the Amygdala and Hypothalmus, but not in Other Regions of the Brain.
5. Impaired Neurogenesis in Obese mice is rescued by Clearance of Senescent Cells with D+Q.
The following is my analysis of this very interesting study. For readers who want the analysis by the authors of the study; they can download the study.
1. As shown in following study, obesity causes metabolic dysfunction and insulin resistance.
2. Insulin resistance causes high insulin, glucose intolerance which results in high mTOR1.
3. High insulin, high mTOR, high glucose causes development of senescents cells in amygdala. Amygdala is emotion center and dysfunction can result in anxiety.
4. High Insulin, high mTOR causes development of senescent glial cells in the proximity of lateral ventricles an area in which ADULT Neurogenesis occurs.
5. D+Q cross the blood brain barrier and cleared senescent cells which ameliorated anxiety from Amygdala dysfunction due to senescent cells and restored neurogenesis.
Conclusion by the authors of study: Anxiety, depression, suicide is associated with obesity. "Here, we show that cellular senescence provides a potential explanation for increased anxiety in obese individuals and that targeting senescence cells holds promise as a therapeutic strategy."
Palmer, Kirkland, 2019.
Introduction: (AG) There is nothing wrong with healthy adipose tissue. However, with age, many people accumulate pathologic adipose tissue. Healthy adipose tissue tends to be subcutaneous and symmetrical. Pathologic adipose tissue tends to have a visceral location and is associated with increasing waistline size. Pathologic adipose tissue is very strongly associated with insulin resistance.
The accumulation of pathologic adipose tissue in older persons, which presents clinically as midline obesity and insulin resistance is a major cause of age-related morbidity causing type 2 diabetes, cardiovascular disease and it accelerates development of most age-related diseases.
Age-related midline obesity is a senescent cell disease.
They used D+Q to target senescent adipose tissue. D+Q was administered for 3 days, followed by14 day free interval and then 3 day D+Q cycle was repeated.
They state: "We employed the combination of D plus Q because...D selectively targets senescent adipose progenitors, a key cell type for adipose tissue and metabolic function. On the other hand, Q, unlike D, is effective against senescent endothetial cells, a cell type implicated in vascular complication of diabetes. D+Q is effective in alleviating multiple age and senescence-associated disorders including...arteriosclerosis, vascular hyporeactivity, osteoporosis, hepatic steatosis, physical dysfunction, neurodegeneration and neuropsychiatric dysfunction."
1. Senescent cells accumulate in visceral fat in obesity.
2. Senescent cell clearance improves insulin sensitivity.
3. Adipogenic potential is improved after senescent cell reduction.
This is ability to make healthy adipose tissue which is insulin sensitive.
4. Macrophage abundance is correlated with senescent cell burden in adipose tissue.
Senescent cells attract macrophages which then contribute to inflammation.
5. Senescent cell clearance decreases macrophage homing to adipose tissue.
6. Decreasing senescent cell burden improved cardiac and renal function in this study.
Conclusion: "Our results implicate cellular senescence as a causal factor in obesity-related inflammation and metabolic derangements and show that emerging senolytic agents (D+Q) hold promise for treating obesity-related metabolic dysfunction and its complications."
AG comment: Targeting senescent cells should be part of treating obesity complicated by insulin resistance.
Farr, James Kirkland, 2017.
This study investigates the role of senescent cells in age-related bone loss by multiple approaches.
The study includes the use of dasatinib and quercetin to prevent bone loss in an approach applicable to humans.
Age-related osteoporosis resulting in pathological fractures with minimal trauma is an enormous public health problem in the aging population. In addition to the morbidity associated with fractures, up to 25% of the elderly hip fractures patients die within a year of this devastating event.
Senescent osteocytes cause the following effects:
1. Senescent osteocytes accumulate in old age
2. Senescent osteocytes secrete SASP.
3. SASP results in the activation and increase in number of osteoclasts which destroy bone.
4. SASP results in the decrease in activity of osteoblasts which make new bone.
5. The net effect of senescent osteocytes is loss of trabecular bone and thinning of cortical bone resulting in fractures with minimal trauma.
After 18 months of age mice have a marked accumulation of senescent osteocytes and develop osteoporosis.
In This study D+Q was administered orally to 20-month old mice once monthly for 4 months. At the end of 4 month treatment D+Q results in decrease in osteoclast numbers, increase in osteoblasts numbers, increase in bone formation, higher femur cortical thickness, increase trabecular thickness, better bone microarchitecture, increased bone strength.
"Senolytic (D+Q) reduce senescent cells, which in turn suppress bone resorption with either an increase in cortical bone or maintenance of trabecular bone formation"... "Our study provides a critical proof-of-concept for the feasibility of this approach for treatment of age-related bone loss."