Aging, Lifespan & Longevity

While the elderly segment of the population continues growing in importance, neurodegenerative diseases increase exponentially. Lifestyle factors such as nutrition, exercise, and education, among others, influence ageing progression, throughout life. Notably, the Central Nervous System (CNS) can benefit from nutritional strategies and dietary interventions that prevent signs of senescence, such as cognitive decline or neurodegenerative diseases such as Alzheimer's disease and Parkinson's...

Recent epidemiological studies in Sweden, a country with traditionally high milk consumption, revealed that the intake of non-fermented pasteurized milk increased all-cause mortality in a dose-dependent manner. In contrast, the majority of epidemiological and clinical studies report beneficial health effects of fermented milk products, especially of yogurt. It is the intention of this review to delineate potential molecular aging mechanisms related to the intake of non-fermented milk versus...

Large studies such as UK Biobank are increasingly used for GWAS and Mendelian randomization (MR) studies. However, selection into and dropout from studies may bias genetic and phenotypic associations. We examine genetic factors affecting participation in four optional components in up to 451,306 UK Biobank participants. We used GWAS to identify genetic variants associated with participation, MR to estimate effects of phenotypes on participation, and genetic correlations to compare participation...

The regulation of telomere length in mammals is crucial for chromosome end-capping and thus for maintaining genome stability and cellular lifespan. This process requires coordination between telomeric protein complexes and the ribonucleoprotein telomerase, which extends the telomeric DNA. Telomeric proteins modulate telomere architecture, recruit telomerase to accessible telomeres and orchestrate the conversion of the newly synthesized telomeric single-stranded DNA tail into double-stranded DNA....

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Obesity and Aging: Molecular Mechanisms and Therapeutic Approaches.

Ageing Res Rev. 2021 Feb 05;:101268

Authors: Santos AL, Sinha S

Abstract
The epidemic of obesity is a major challenge for health policymakers due to its far-reaching effects on population health and potentially overwhelming financial burden on healthcare systems. Obesity is associated with an increased risk of developing acute and chronic diseases, including hypertension, stroke, myocardial infarction, cardiovascular disease, diabetes, and cancer. Interestingly, the metabolic dysregulation associated with obesity is similar to that observed in normal aging, and substantial evidence suggests the potential of obesity to accelerate aging. Therefore, understanding the mechanism of fat tissue dysfunction in obesity could provide insights into the processes that contribute to the metabolic dysfunction associated with the aging process. Here, we review the molecular and cellular mechanisms underlying both obesity and aging, and how obesity and aging can predispose individuals to chronic health complications. The potential of lifestyle and pharmacological interventions to counter obesity and obesity-related pathologies, as well as aging, is also addressed.

PMID: 33556548 [PubMed - as supplied by publisher]

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To breathe or not to breathe: understanding how oxygen sensing contributes to age-related phenotypes.

Ageing Res Rev. 2021 Feb 05;:101267

Authors: van Vliet T, Casciaro F, Demaria M

Abstract
Aging is characterized by a progressive loss of tissue integrity and functionality due to disrupted homeostasis. Molecular oxygen is pivotal to maintain tissue functions, and aerobic species have evolved a sophisticated sensing system to ensure proper oxygen supply and demand. It is not surprising that aberrations in oxygen and oxygen-associated pathways subvert health and promote different aspects of aging. In this review, we discuss emerging findings on how oxygen-sensing mechanisms regulate different cellular and molecular processes during normal physiology, and how dysregulation of oxygen availability lead to disease and aging. We describe various clinical manifestations associated with deregulation of oxygen balance, and how oxygen-modulating therapies and natural oxygen oscillations influence longevity. We conclude by discussing how a better understanding of oxygen-related mechanisms that orchestrate aging processes may lead to the development of new therapeutic strategies to extend healthy aging.

PMID: 33556549 [PubMed - as supplied by publisher]

Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer's...

This study provides a quantitative synthesis of the prospective associations between personality traits (neuroticism, extraversion, openness, agreeableness, conscientiousness) and the risk of incident Alzheimer's disease and related dementias. We conducted five separate meta-analyses with 8-12 samples (N = 30,036 to 33,054) that were identified through a systematic literature search following the MOOSE guidelines. Higher neuroticism (HR = 1.24, 95% CI [1.17, 1.31]) and lower conscientiousness...

Macroautophagy/autophagy plays a critical role in restoring/maintaining skeletal muscle function under normal conditions as well as during damage-induced regeneration. This homeostatic degradation mechanism, however, rapidly declines with aging leading to functional deterioration of skeletal muscles. ARHGEF3 is a RHOA- and RHOB-specific GEF capable of inhibiting myogenic AKT signaling independently of its GEF function. Our recent study reveals that ARHGEF3 negatively regulates skeletal muscle...

Biological clocks have been developed at different molecular levels and were found to be more advanced in the presence of somatic illness and mental disorders. However, it is unclear whether different biological clocks reflect similar aging processes and determinants. In ~3000 subjects, we examined whether five biological clocks (telomere length, epigenetic, transcriptomic, proteomic, and metabolomic clocks) were interrelated and associated to somatic and mental health determinants. Correlations...

Personality traits predict important life outcomes, such as success in love and work life, well-being, health, and longevity. Given these positive relations to important outcomes, economists, policy makers, and scientists have proposed intervening to change personality traits to promote positive life outcomes. However, nonclinical interventions to change personality traits are lacking so far in large-scale naturalistic populations. This study (n = 1,523) examined the effects of a 3-mo digital...

Alterations in nuclear shape are present in human diseases and ageing. A compromised nuclear lamina is molecularly interlinked to altered chromatin functions and genomic instability. Whether these alterations are a cause or a consequence of the pathological state are important questions in biology. Here, we summarize the roles of nuclear envelope components in chromatin organization, phase separation and transcriptional and epigenetic regulation. Examining these functions in healthy backgrounds...

Age-related diseases such as cancer, cardiovascular disease, kidney failure, and osteoarthritis have universal features: Their incidence rises exponentially with age with a slope of 6-8% per year and decreases at very old ages. There is no conceptual model which explains these features in so many diverse diseases in terms of a single shared biological factor. Here, we develop such a model, and test it using a nationwide medical record dataset on the incidence of nearly 1000 diseases over 50...

As they age, adult stem cells become more prone to functional decline, which is responsible for aging-associated tissue degeneration and diseases. One goal of aging research is to identify drugs that can repair age-associated tissue degeneration. Multiple organ development-related signaling pathways have recently been demonstrated to have functions in tissue homeostasis and aging process. Therefore, in this study, we tested several chemicals that are essential for organ development to assess...

CONCLUSIONS: In this study, intakes of eggs and cholesterol were associated with higher all-cause, CVD, and cancer mortality. The increased mortality associated with egg consumption was largely influenced by cholesterol intake. Our findings suggest limiting cholesterol intake and replacing whole eggs with egg whites/substitutes or other alternative protein sources for facilitating cardiovascular health and long-term survival.

Pregnancy-associated plasma protein-A (PAPP-A) is a secreted metalloprotease that increases insulin-like growth factor (IGF) availability by cleaving IGF-binding proteins. Reduced IGF signaling extends longevity in multiple species, and consistent with this, PAPP-A deletion extends lifespan and healthspan; however, the mechanism remains unclear. To clarify PAPP-A's role, we developed a PAPP-A neutralizing antibody and treated adult mice with it. Transcriptomic profiling across tissues showed...

In this issue of Developmental Cell, Zou et al. utilize eyelid samples to examine human skin aging at the single-cell level. They discover photo- and inflammation-related changes already in middle age and find that restoring youthful expression of KLF6 and HES1 may dial back some age-associated changes.

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Replacing conventional battery electrolyte additives with dioxolone derivatives for high-energy-density lithium-ion batteries.

Nat Commun. 2021 Feb 05;12(1):838

Authors: Park S, Jeong SY, Lee TK, Park MW, Lim HY, Sung J, Cho J, Kwak SK, Hong SY, Choi NS

Abstract
Solid electrolyte interphases generated using electrolyte additives are key for anode-electrolyte interactions and for enhancing the lithium-ion battery lifespan. Classical solid electrolyte interphase additives, such as vinylene carbonate and fluoroethylene carbonate, have limited potential for simultaneously achieving a long lifespan and fast chargeability in high-energy-density lithium-ion batteries (LIBs). Here we report a next-generation synthetic additive approach that allows to form a highly stable electrode-electrolyte interface architecture from fluorinated and silylated electrolyte additives; it endures the lithiation-induced volume expansion of Si-embedded anodes and provides ion channels for facile Li-ion transport while protecting the Ni-rich LiNi0.8Co0.1Mn0.1O2 cathodes. The retrosynthetically designed solid electrolyte interphase-forming additives, 5-methyl-4-((trifluoromethoxy)methyl)-1,3-dioxol-2-one and 5-methyl-4-((trimethylsilyloxy)methyl)-1,3-dioxol-2-one, provide spatial flexibility to the vinylene carbonate-derived solid electrolyte interphase via polymeric propagation with the vinyl group of vinylene carbonate. The interface architecture from the synthesized vinylene carbonate-type additive enables high-energy-density LIBs with 81.5% capacity retention after 400 cycles at 1 C and fast charging capability (1.9% capacity fading after 100 cycles at 3 C).

PMID: 33547320 [PubMed - as supplied by publisher]

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Early growth response 2 (EGR2) is a novel regulator of the senescence programme.

Aging Cell. 2021 Feb 06;:e13318

Authors: Tyler EJ, Gutierrez Del Arroyo A, Hughes BK, Wallis R, Garbe JC, Stampfer MR, Koh J, Lowe R, Philpott MP, Bishop CL

Abstract
Senescence, a state of stable growth arrest, plays an important role in ageing and age-related diseases in vivo. Although the INK4/ARF locus is known to be essential for senescence programmes, the key regulators driving p16 and ARF transcription remain largely underexplored. Using siRNA screening for modulators of the p16/pRB and ARF/p53/p21 pathways in deeply senescent human mammary epithelial cells (DS HMECs) and fibroblasts (DS HMFs), we identified EGR2 as a novel regulator of senescence. EGR2 expression is up-regulated during senescence, and its ablation by siRNA in DS HMECs and HMFs transiently reverses the senescent phenotype. We demonstrate that EGR2 activates the ARF and p16 promoters and directly binds to both the ARF and p16 promoters. Loss of EGR2 down-regulates p16 levels and increases the pool of p16- p21- 'reversed' cells in the population. Moreover, EGR2 overexpression is sufficient to induce senescence. Our data suggest that EGR2 is a direct transcriptional activator of the p16/pRB and ARF/p53/p21 pathways in senescence and a novel marker of senescence.

PMID: 33547862 [PubMed - as supplied by publisher]

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Pathological angiogenesis in retinopathy engages cellular senescence and is amenable to therapeutic elimination via BCL-xL inhibition.

Cell Metab. 2021 Feb 02;:

Authors: Crespo-Garcia S, Tsuruda PR, Dejda A, Ryan RD, Fournier F, Chaney SY, Pilon F, Dogan T, Cagnone G, Patel P, Buscarlet M, Dasgupta S, Girouard G, Rao SR, Wilson AM, O'Brien R, Juneau R, Guber V, Dubrac A, Beausejour C, Armstrong S, Mallette FA, Yohn CB, Joyal JS, Marquess D, Beltran PJ, Sapieha P

Abstract
Attenuating pathological angiogenesis in diseases characterized by neovascularization such as diabetic retinopathy has transformed standards of care. Yet little is known about the molecular signatures discriminating physiological blood vessels from their diseased counterparts, leading to off-target effects of therapy. We demonstrate that in contrast to healthy blood vessels, pathological vessels engage pathways of cellular senescence. Senescent (p16INK4A-expressing) cells accumulate in retinas of patients with diabetic retinopathy and during peak destructive neovascularization in a mouse model of retinopathy. Using either genetic approaches that clear p16INK4A-expressing cells or small molecule inhibitors of the anti-apoptotic protein BCL-xL, we show that senolysis suppresses pathological angiogenesis. Single-cell analysis revealed that subsets of endothelial cells with senescence signatures and expressing Col1a1 are no longer detected in BCL-xL-inhibitor-treated retinas, yielding a retina conducive to physiological vascular repair. These findings provide mechanistic evidence supporting the development of BCL-xL inhibitors as potential treatments for neovascular retinal disease.

PMID: 33548171 [PubMed - as supplied by publisher]