Maintenance and repair of an aging life cycle

Baar, Marjolein P.; Willigenburg, Hester van; Keizer, Peter L.J. de

doi:10.18632/oncotarget.18046

Cited by 6 publications

(5 citation statements)

References 7 publications

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“…Some authors suggest that physiological aging (or senescence) is not really distinguishable from pathology ( 273 ), while others argue that aging is different from age-related diseases and other pathologies ( 274 , 275 ). It is interesting to stress that the answer to this question has important theoretical and practical consequences, taking into account that various strategies capable of setting back the aging clock are emerging ( 276 – 278 ). The most relevant consequence is that, if we agree that aging is equal to disease, all human beings have to be considered as patients to be treated, being an open question when this treatment should start.…”

Section: Discussionmentioning

confidence: 99%

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

et al. 2018

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Geroscience, the new interdisciplinary field that aims to understand the relationship between aging and chronic age-related diseases (ARDs) and geriatric syndromes (GSs), is based on epidemiological evidence and experimental data that aging is the major risk factor for such pathologies and assumes that aging and ARDs/GSs share a common set of basic biological mechanisms. A consequence is that the primary target of medicine is to combat aging instead of any single ARD/GSs one by one, as favored by the fragmentation into hundreds of specialties and sub-specialties. If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, a major question emerges: which is the difference, if any, between aging and ARDs/GSs? The hypothesis that ARDs and GSs such as frailty can be conceptualized as accelerated aging will be discussed by analyzing in particular frailty, sarcopenia, chronic obstructive pulmonary disease, cancer, neurodegenerative diseases such as Alzheimer and Parkinson as well as Down syndrome as an example of progeroid syndrome. According to this integrated view, aging and ARDs/GSs become part of a continuum where precise boundaries do not exist and the two extremes are represented by centenarians, who largely avoided or postponed most ARDs/GSs and are characterized by decelerated aging, and patients who suffered one or more severe ARDs in their 60s, 70s, and 80s and show signs of accelerated aging, respectively. In between these two extremes, there is a continuum of intermediate trajectories representing a sort of gray area. Thus, clinically different, classical ARDs/GSs are, indeed, the result of peculiar combinations of alterations regarding the same, limited set of basic mechanisms shared with the aging process. Whether an individual will follow a trajectory of accelerated or decelerated aging will depend on his/her genetic background interacting lifelong with environmental and lifestyle factors. If ARDs and GSs are manifestations of accelerated aging, it is urgent to identify markers capable of distinguishing between biological and chronological age to identify subjects at higher risk of developing ARDs and GSs. To this aim, we propose the use of DNA methylation, N-glycans profiling, and gut microbiota composition to complement the available disease-specific markers.

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Section: Discussionmentioning

confidence: 99%

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

et al. 2018

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“…Additional treatment strategies targeted at reducing cellular senescence early in the time course of transplantation and long-term are desirable. As a basis, a healthy life-style with regular physical exercise and dietary interventions should be promoted since this has been shown to improve metabolic parameters such as insulin sensitivity and lipid profile and to reduce DNA damage as well as oxidative stress as potential mechanisms to delay age related senescence [ 4 , 48 ]. Recently, a novel strategy to reduce the senescent burden by therapeutic elimination of senescent cells is emerging.…”

Section: Discussionmentioning

confidence: 99%

The mTOR inhibitor Rapamycin protects from premature cellular senescence early after experimental kidney transplantation

et al. 2022

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Interstitial fibrosis and tubular atrophy, a major cause of kidney allograft dysfunction, has been linked to premature cellular senescence. The mTOR inhibitor Rapamycin protects from senescence in experimental models, but its antiproliferative properties have raised concern early after transplantation particularly at higher doses. Its effect on senescence has not been studied in kidney transplantation, yet. Rapamycin was applied to a rat kidney transplantation model (3 mg/kg bodyweight loading dose, 1.5 mg/kg bodyweight daily dose) for 7 days. Low Rapamycin trough levels (2.1–6.8 ng/mL) prevented the accumulation of p16INK4a positive cells in tubules, interstitium, and glomerula. Expression of the cytokines MCP-1, IL-1β, and TNF-α, defining the proinflammatory senescence-associated secretory phenotype, was abrogated. Infiltration with monocytes/macrophages and CD8+ T-lymphocytes was reduced and tubular function was preserved by Rapamycin. Inhibition of mTOR was not associated with impaired structural recovery, higher glucose levels, or weight loss. mTOR inhibition with low-dose Rapamycin in the immediate posttransplant period protected from premature cellular senescence without negative effects on structural and functional recovery from preservation/reperfusion damage, glucose homeostasis, and growth in a rat kidney transplantation model. Reduced senescence might maintain the renal regenerative capacity rendering resilience to future injuries resulting in protection from interstitial fibrosis and tubular atrophy.

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“…2b: PCA representation of the 352-gene classi er across the SCOPE cohort) and highlighting the potential use of this classi er to distinguish Senescent-INRs in clinical settings. Our classi er (Table S11) included genes that drive a senescent biology (FOXO3, FOXO4, TGFBR2, RIOK3, IRF3 and BCL2L1) 46,59,60,61 and regulators of mitochondrial activity (NDUFS3, CYB5R3, ATP5G2) 62 . Several transporters of macromolecules: SLC6A8 (Sodium-and chloride-dependent creatine transporter 1 63 ), SLC48A1 (Heme transporter 64 ), SLC4A1 (Band 3 anion transporter 65 ), SLC25A23 (Mitochondrial Calcium carrier 66 ) and SLC38A5 (glucose 67 ) upregulated in Senescent-INRs and were also features of the classi er (Table S11).…”

Section: Classi Er Con Rms the Generalizability Of The Senescent-inr Phenotype In Hiv-infected Subjectsmentioning

confidence: 99%

TGF-β associated senescence and impaired metabolism in central memory CD4 T cells promotes HIV persistence

Sékaly

Ghneim

Sharma

et al. 2021

Preprint

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Current therapeutic interventions to eradicate latent HIV (“reservoir”) and restore immune function in ART-treated HIV infection have yet to show efficacy. To explore mechanisms of HIV persistence, we apply an integrated systems biology approach and identify a distinct group of individuals with poor CD4 T-cell reconstitution (Immunologic non-responders, “INRs”) and high frequencies of cells with inducible HIV. Contrary to the prevailing notion that immune activation drives HIV persistence and immune dysfunction, peripheral blood leukocytes from these subjects have enhanced expression of a network of genes regulated by cellular senescence. In these subjects, increased frequencies of regulatory T cells and expression of the TGF-β signaling cascade are concomitant with the downregulation of cell cycle and metabolism in CD4 central memory T (TCM) cells. These cascades, downstream of TGF-β, lead to the accumulation of PD-1 expressing CD4 TCM and are associated with an increase in frequencies of cells with inducible HIV ex vivo. In vitro validation confirmed that this cellular profile was driven by a β-hydroxybutyrates/bile acid rich metabolic milieu and resulted in TGF-β associated latency establishment. Our findings identify targets for PD-1 or TGF-β specific interventions that can overcome cellular senescence; these therapeutic approaches have shown safety and efficacy in cancer, and may prove to be crucial for HIV eradication.

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Maintenance and repair of an aging life cycle

Cited by 6 publications

References 7 publications

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

The Continuum of Aging and Age-Related Diseases: Common Mechanisms but Different Rates

The mTOR inhibitor Rapamycin protects from premature cellular senescence early after experimental kidney transplantation

TGF-β associated senescence and impaired metabolism in central memory CD4 T cells promotes HIV persistence

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