Abstract:With ageing, there is a loss of adult stem cell function. However, there is no direct evidence that this has a causal role in ageing-related decline. We tested this using muscle-derived stem/progenitor cells (MDSPCs) in a murine progeria model. Here we show that MDSPCs from old and progeroid mice are defective in proliferation and multilineage differentiation. Intraperitoneal administration of MDSPCs, isolated from young wild-type mice, to progeroid mice confer significant lifespan and healthspan extension. Th… Show more
“…Only a few of the injected, labeled MDSPCs were found in different tissues with no evidence of differentiation, suggesting that the therapeutic effect of MDSPCs is likely mediated by secreted factors that act systemically in a cell nonautonomous manner. Consistent with this hypothesis, coculture of young, functional MDSPCs with old MDSPCs in a transwell system resulted in improvement in the ability of the old MDSPCs to proliferate and differentiate (11). At least part of this activity co-purifies with EVs.…”
Section: Stem Cells and Agingsupporting
confidence: 60%
“…Reduction of the senescent cell burden can lead to reduced inflammation, decreased macromolecular dysfunction, and enhanced function of progenitors (8)(9)(10). Also, adult stem cells become dysfunctional with evidence of senescence with age, likely driven by macromolecular and organelle dysfunction (11). These four biological processes are also the key components of the seven pillars of aging, defined as adaption to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis and stem cells and regeneration.…”
Section: Mechanisms Underlying Agingmentioning
confidence: 99%
“…Similarly, MSCs derived from the bone marrow of patients with Hutchinson-Gilford Progeroid Syndrome, a disease of accelerated aging, are defective in their ability to differentiate (41). In addition, muscle derived stem/progenitor cells (MDSPC) are adversely affected in accelerated and natural aged mice, displaying loss of proliferation and ability to differentiate in culture (11,42). Importantly, this dysfunction was demonstrated to directly contribute to age-related degenerative changes since intraperitoneal injection of only 106 functional, young MDSPCs was sufficient to extend healthspan and lifespan in two different mouse models of accelerated aging (11).…”
Section: Stem Cells and Agingmentioning
confidence: 99%
“…In addition, muscle derived stem/progenitor cells (MDSPC) are adversely affected in accelerated and natural aged mice, displaying loss of proliferation and ability to differentiate in culture (11,42). Importantly, this dysfunction was demonstrated to directly contribute to age-related degenerative changes since intraperitoneal injection of only 106 functional, young MDSPCs was sufficient to extend healthspan and lifespan in two different mouse models of accelerated aging (11). Only a few of the injected, labeled MDSPCs were found in different tissues with no evidence of differentiation, suggesting that the therapeutic effect of MDSPCs is likely mediated by secreted factors that act systemically in a cell nonautonomous manner.…”
AgingIt is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. As a consequence, the incidence of numerous debilitating diseases increases nearly exponentially with age, including cardiovascular disease, neurodegeneration, diabetes, osteoarthritis, and osteoporosis. Over 90% of individuals >65 years of age have at least one chronic disease, while >70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Indeed, chronic diseases of the elderly are the greatest healthcare burden in the United States and seriously impact the quality of life of a large segment of the population. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics. Given the diverse roles of blood-borne EVs in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process. This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging. Abstract: Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system. As our world population ages dramatically over the next decades, this will only increase.Hence, there is a great need to discover fundamental mechanisms of aging to enable development of strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond to it by triggering individual cell fate decisions that ultimately disrupt tissue homeostasis and thus increase risk of morbidity. However, there are numerous lines of evidence, including heterochronic parabiosis and plasma transfer, indicating that cell non-autonomous mechanisms are critically important for aging as well. In addition, senescent cells, which accumulate in tissues with age, can display a senescence-associated secretory phenotype (SASP) that contributes to driving aging and loss of tissue homeostasis through a non-cell autonomous mechanism(s). Given the diverse roles of blood-borne extracellular vesicles (EVs) in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process through cell non-autonomous mechanisms. The fact that senescent cells release more EVs and with a different composition suggests they contribute to the adverse effects of senescence on aging. In addition, the ability of EVs from functional progenitor cells to promote tissue regeneration suggests that stem cell-derived EVs could be used therapeutica...
“…Only a few of the injected, labeled MDSPCs were found in different tissues with no evidence of differentiation, suggesting that the therapeutic effect of MDSPCs is likely mediated by secreted factors that act systemically in a cell nonautonomous manner. Consistent with this hypothesis, coculture of young, functional MDSPCs with old MDSPCs in a transwell system resulted in improvement in the ability of the old MDSPCs to proliferate and differentiate (11). At least part of this activity co-purifies with EVs.…”
Section: Stem Cells and Agingsupporting
confidence: 60%
“…Reduction of the senescent cell burden can lead to reduced inflammation, decreased macromolecular dysfunction, and enhanced function of progenitors (8)(9)(10). Also, adult stem cells become dysfunctional with evidence of senescence with age, likely driven by macromolecular and organelle dysfunction (11). These four biological processes are also the key components of the seven pillars of aging, defined as adaption to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis and stem cells and regeneration.…”
Section: Mechanisms Underlying Agingmentioning
confidence: 99%
“…Similarly, MSCs derived from the bone marrow of patients with Hutchinson-Gilford Progeroid Syndrome, a disease of accelerated aging, are defective in their ability to differentiate (41). In addition, muscle derived stem/progenitor cells (MDSPC) are adversely affected in accelerated and natural aged mice, displaying loss of proliferation and ability to differentiate in culture (11,42). Importantly, this dysfunction was demonstrated to directly contribute to age-related degenerative changes since intraperitoneal injection of only 106 functional, young MDSPCs was sufficient to extend healthspan and lifespan in two different mouse models of accelerated aging (11).…”
Section: Stem Cells and Agingmentioning
confidence: 99%
“…In addition, muscle derived stem/progenitor cells (MDSPC) are adversely affected in accelerated and natural aged mice, displaying loss of proliferation and ability to differentiate in culture (11,42). Importantly, this dysfunction was demonstrated to directly contribute to age-related degenerative changes since intraperitoneal injection of only 106 functional, young MDSPCs was sufficient to extend healthspan and lifespan in two different mouse models of accelerated aging (11). Only a few of the injected, labeled MDSPCs were found in different tissues with no evidence of differentiation, suggesting that the therapeutic effect of MDSPCs is likely mediated by secreted factors that act systemically in a cell nonautonomous manner.…”
AgingIt is estimated that in the next 20 years, the number of individuals in the United States over the age of 65 will double, numbering more than 70 million individuals. Unfortunately, as we age there is an unavoidable and progressive loss of the ability to maintain tissue homeostasis under stress and an attrition of functional reserve. As a consequence, the incidence of numerous debilitating diseases increases nearly exponentially with age, including cardiovascular disease, neurodegeneration, diabetes, osteoarthritis, and osteoporosis. Over 90% of individuals >65 years of age have at least one chronic disease, while >70% have at least two. These chronic diseases account for 75% of our healthcare costs, amounting to approximately $3 trillion in costs last year alone. Indeed, chronic diseases of the elderly are the greatest healthcare burden in the United States and seriously impact the quality of life of a large segment of the population. Thus, there is a significant need to understand mechanisms driving aging and to develop novel therapeutics. Given the diverse roles of blood-borne EVs in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process. This review focuses on the role EVs could play in aging, their therapeutic application for extending healthspan and their potential for use as biomarkers of unhealthy aging. Abstract: Aging and the chronic diseases associated with aging place a tremendous burden on our healthcare system. As our world population ages dramatically over the next decades, this will only increase.Hence, there is a great need to discover fundamental mechanisms of aging to enable development of strategies for minimizing the impact of aging on our health and economy. There is general agreement that cell autonomous mechanisms contribute to aging. As cells accrue damage over time, they respond to it by triggering individual cell fate decisions that ultimately disrupt tissue homeostasis and thus increase risk of morbidity. However, there are numerous lines of evidence, including heterochronic parabiosis and plasma transfer, indicating that cell non-autonomous mechanisms are critically important for aging as well. In addition, senescent cells, which accumulate in tissues with age, can display a senescence-associated secretory phenotype (SASP) that contributes to driving aging and loss of tissue homeostasis through a non-cell autonomous mechanism(s). Given the diverse roles of blood-borne extracellular vesicles (EVs) in modulating not only the immune response, but also angiogenesis and tissue regeneration, they likely play a key role in modulating the aging process through cell non-autonomous mechanisms. The fact that senescent cells release more EVs and with a different composition suggests they contribute to the adverse effects of senescence on aging. In addition, the ability of EVs from functional progenitor cells to promote tissue regeneration suggests that stem cell-derived EVs could be used therapeutica...
“…Ercc1 −/Δ mice that model XFE progeroid syndrome develop conditions common in elderly humans such as osteoporosis, pulmonary fibrosis, chronic kidney disease, cardiovascular disease, muscle wasting, peripheral neuropathy, hepatic fibrosis, urinary incontinence, intervertebral disc degeneration, cognitive decline, and loss of hearing and vision [6,9–13]. In addition, multiple therapeutic interventions have been demonstrated to extend the health span of Ercc1 −/Δ mice [14,15], including anti-geronic therapeutics and senolytics [16,17]. This establishes Ercc1 −/Δ mice as a rapid model system for identifying therapeutics that delay age-related diseases.10.1080/20010001.2018.1524815-F0001Figure 1.Advantages of studying Alzheimer’s disease in the Ercc1 −/Δ progeria mouse.…”
The prevalence of Alzheimer’s disease (AD) is expected to dramatically increase in older people worldwide. Efforts to find disease-modifying treatments have been largely unsuccessful because of the focus on disease-specific pathogenesis, and lack of animal models to study AD in the context of aging and age-related co-morbidities. The geroscience approach to studying AD would suggest that modulation of aging per se would be a useful strategy, but a mammalian model system that combines both aging and AD is not available. One approach to study old age and AD is to utilize murine models of progeroid syndrome, which can provide a number of advantages not only for basic aging biology but also for preclinical drug testing. A progeria background, such as the Ercc1 mutant mouse (Ercc1−/Δ), provides an aging component not seen in current murine models of AD that lack age-related co-morbidities typical of AD patients.Ercc1−/Δ mice experience the same types of stochastic endogenous DNA damage as WT mice, but accumulate lesions faster due to impaired DNA repair, which accelerates the normal aging process by 6-fold. These mice do not show frank AD pathology but represent a predisposed or hypersensitive environment for AD pathology, where pathogenic elements of AD can be introduced, either by crossing with well-established AD transgenic mouse lines, or transcranial stereotaxic delivery directly into the brain. Since Ercc1−/Δ mice age five to six times faster than WT mice, very rapid characterization and testing of therapeutic interventions is possible. Studies are urgently needed to capitalize on the highly informative potential of this novel AD mouse model.
Epidemiological studies indicate that aging is associated with an increased incidence of a variety of chronic lung diseases affecting a significant portion of the population [1,2,3,4,5]. The prevalence of chronic obstructive pulmonary disease (COPD) increases with age for both men and women throughout most of the lifespan, with the highest prevalence among individuals aged 65-84 [6, 7]. In 2005, approximately 1 in 20 deaths in the United States had COPD as the underlying cause [5]. Similarly, the occurrence of idiopathic pulmonary fibrosis (IPF) increases in both prevalence and incidence in the sixth decade of life. Symptoms typically occur at the age of 50 to 70 years, and most patients are greater than60 years of age at the time of clinical presentation [2,8]. Notably, both of the aforementioned diseases show an increased deposition of collagen and fibrotic tissue albeit in different locations of sometimes the same lung, suggesting common, at least in part, molecular mechanisms of pathogenesis. Currently, only limited therapeutic strategies exist to treat chronic lung diseases, most of which are symptomatic instead of causal.Although not a chronic lung disease, acute respiratory distress syndrome (ARDS) is a very common clinical entity and a major cause of morbidity and mortality in the critical care setting especially for the elderly patients. Only in the US, 190,600 new cases of ARDS occur every year [9], and recent studies show an incidence of 306 per 100,000 person-years for people from 75 to 84 years old, compared to 16 cases per 100,000 person-years in teenagers between 15 and 19 years old. Mortality increases from 24% to 60% for those older than 85 years compared to 15-19-year-old patients. Furthermore, younger patients had a better rate of recovery than older patients, but neither group returned to previous level of functionality [10,11,12]. Although existing therapeutic approaches are contributing to the decrease in mortality, they, in many instances, aggravate lung injury.Even if our understanding of the biology of aging has advanced remarkably, the molecular mechanisms linking aging to susceptibility to lung injury and disease remain unclear. Cellular senescence, oxidative stress, abnormal shortening of telomeres, apoptosis, and
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