Mixing old and young: enhancing rejuvenation and accelerating aging

Lau, Ashley; Kennedy, Brian K.; Kirkland, James L.; Tullius, Stefan G.

doi:10.1172/jci123946

Cited by 25 publications

(19 citation statements)

References 90 publications

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“…Therefore, the success of cardiac regenerative therapeutic approaches thus far tested for treating patients with heart failure and disease could be of limited efficacy in promoting myocardial regeneration because of the increased number of senescent, dysfunctional CPCs and cardiomyocytes (Cesselli et al, ; Chimenti et al, ), and the resultant presence of a cardiac SASP in the aged and failing heart that impairs the function of the remaining nonsenescent CPCs. These findings may also have implications regarding the use hearts from aged versus younger donors for transplantation (Lau, Kennedy, Kirkland, Tullius, & S.G., ).…”

Section: Discussionmentioning

confidence: 96%

“…Future work should address the effects of senolytic agents on improving cardiac function and alleviating the SASP, resulting in an improved microenvironment in vivo and the activity of other cell types, such as fibroblasts and endothelial cells. Indeed, next steps should determine whether senolytic approaches could be used in conjunction with cell therapy interventions to improve the environment (the “soil”) that the cells (the “seeds”) are transplanted into and therefore, ameliorate intrinsic reparative mechanistic processes that are compromised with age (Lau et al, ). Indeed, targeting senescent cells could also impact the potency of resident stem/progenitor populations in other aged organs.…”

Section: Discussionmentioning

confidence: 99%

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Aged‐senescent cells contribute to impaired heart regeneration

et al. 2019

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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 (p16INK4A, SA‐β‐gal, DNA damage γH2AX, telomere length, senescence‐associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK‐ATTAC or wild‐type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67‐, EdU‐positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Aged‐senescent cells contribute to impaired heart regeneration

et al. 2019

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“…Diabetes/ Obesity [109,110,112,[116][117][118] Cardiac dysfunction [13,18,114] Vascular hyporeactivity/ calcification [114] AV fistulae [115] Frailty [21,51,52,87] Age-related muscle loss (Sarcopenia) [119] Chemotherapy complications [21,51,93,120,121] Radiation complications [122] Cancers [51] Bone marrow transplant complications [120] Organ transplantation complications [123,124] Myeloma/ MGUS [125] Age-related cognitive dysfunction [126] Alzheimer's disease [23,127] Parkinson's disease [76] Amyotrophic lateral sclerosis [128] Ataxia [87] Obesity-related neuropsychiatric dysfunction [24] Renal dysfunction [111,129] Urinary incontinence [87] Osteoporosis [14,71,130] Osteoarthritis [131] Age-related intervertebral disc disease [87,132] Idiopathic pulmonary fibrosis [21,133]…”

Section: Condition Referencesmentioning

confidence: 99%

Senolytic drugs: from discovery to translation

2020

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“…However, quitting smoking after age 60 was associated with additional stress and increased the risk of earlier death and other outcomes compared to current smokers. This aging effect could represent the declining regenerative capacity of many tissues after middle-age [40,41]. Little is known of how smoking interacts with basic aging processes of cell senescence and systemic inflammation.…”

Section: Plos Onementioning

confidence: 99%

Female vulnerability to the effects of smoking on health outcomes in older people

et al. 2020

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Cigarette smoking is among the leading risk factors for mortality and morbidity. While men have a higher smoking prevalence, mechanistic experiments suggest that women are at higher risk for health problems due to smoking. Moreover, the comparison of smoking effects on multiple conditions and mortality for men and women has not yet been done in a population-based group with race/ethnic diversity. We used proportional hazards models and restricted mean survival time to assess differences in smoking effects by sex for multiple health outcomes using data from the U.S. Health and Retirement Study (HRS), a population-representative cohort of individuals aged 50+ (n = 22,708, 1992-2014). Men had experienced more smoking pack-years than women (22.0 vs 15.6 average pack-years). Age of death, onset of lung disorders, heart disease, stroke, and cancer showed dosedependent effects of smoking for both sexes. Among heavy smokers (>28 pack-years) women had higher risk of earlier age of death (HR = 1.3, 95%CI:1.03-1.65) and stroke (HR = 1.37, 95%CI:1.02-1.83). Risk of cancer and heart disease did not differ by sex for smokers. Women had earlier age of onset for lung disorders (HR = 2.83, 95%CI:1.74-4.6), but men risk due to smoking were higher (Smoking-Sex interaction P<0.02) than women. Passive smoke exposure increased risk of earlier heart disease (HR = 1.33, 95%CI:1.07-1.65) and stroke (HR:1.54, 95%CI:1.07-2.22) for non-smokers, mainly in men. Smoking cessation after 15 years partially attenuated the deleterious smoking effects for all health outcomes. In sum, our results suggest that women are more vulnerable to ever smoking for earlier death and risk of stroke, but less vulnerable for lung disorders. From an epidemiological perspective, sex differences in smoking effects are important considerations that could underlie sex differences in health outcomes. These findings also encourage future mechanistic experiments to resolve potential mechanisms of sex-specific cigarette smoke toxicity. Implications This study identifies new sex differences in health outcomes due to smoking exposures. Sex differences in smoking hazards are often missed in epidemiological studies. Specifically,

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Mixing old and young: enhancing rejuvenation and accelerating aging

Cited by 25 publications

References 90 publications

Aged‐senescent cells contribute to impaired heart regeneration

Aged‐senescent cells contribute to impaired heart regeneration

Senolytic drugs: from discovery to translation

Female vulnerability to the effects of smoking on health outcomes in older people

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