Aging, Lifespan & Longevity

Beware of thy neighbor: Senescent cancer cells feast on adjacent cells to persist.

J Cell Biol. 2019 Oct 18;:

Authors: Napoli M, Flores ER

Abstract
Chemotherapy-resistant tumor cells are responsible for poor patient outcome. In this issue, Tonnessen-Murray et al. (2019. J. Cell Biol https://doi.org/10.1083/jcb.201904051) elegantly show that chemotherapy triggers macrophage-like features in surviving cancer cells, which in turn phagocyte normal and tumor cells alike to outlast dormancy and cause relapse.

PMID: 31628158 [PubMed - as supplied by publisher]

NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice.

Aging Cell. 2019 Oct 18;:e13050

Authors: Marín-Aguilar F, Lechuga-Vieco AV, Alcocer-Gómez E, Castejón-Vega B, Lucas J, Garrido C, Peralta-Garcia A, Pérez-Pulido AJ, Varela-López A, Quiles JL, Ryffel B, Flores I, Bullón P, Ruiz-Cabello J, Cordero MD

Abstract
While NLRP3-inflammasome has been implicated in cardiovascular diseases, its role in physiological cardiac aging is largely unknown. During aging, many alterations occur in the organism, which are associated with progressive impairment of metabolic pathways related to insulin resistance, autophagy dysfunction, and inflammation. Here, we investigated the molecular mechanisms through which NLRP3 inhibition may attenuate cardiac aging. Ablation of NLRP3-inflammasome protected mice from age-related increased insulin sensitivity, reduced IGF-1 and leptin/adiponectin ratio levels, and reduced cardiac damage with protection of the prolongation of the age-dependent PR interval, which is associated with atrial fibrillation by cardiovascular aging and reduced telomere shortening. Furthermore, old NLRP3 KO mice showed an inhibition of the PI3K/AKT/mTOR pathway and autophagy improvement, compared with old wild mice and preserved Nampt-mediated NAD+ levels with increased SIRT1 protein expression. These findings suggest that suppression of NLRP3 prevented many age-associated changes in the heart, preserved cardiac function of aged mice and increased lifespan.

PMID: 31625260 [PubMed - as supplied by publisher]

The Machado-Joseph disease deubiquitylase ataxin-3 interacts with LC3C/GABARAP and promotes autophagy.

Aging Cell. 2019 Oct 17;:e13051

Authors: Herzog LK, Kevei É, Marchante R, Böttcher C, Bindesbøll C, Lystad AH, Pfeiffer A, Gierisch ME, Salomons FA, Simonsen A, Hoppe T, Dantuma NP

Abstract
The pathology of spinocerebellar ataxia type 3, also known as Machado-Joseph disease, is triggered by aggregation of toxic ataxin-3 (ATXN3) variants containing expanded polyglutamine repeats. The physiological role of this deubiquitylase, however, remains largely unclear. Our recent work showed that ATX-3, the nematode orthologue of ATXN3, together with the ubiquitin-directed segregase CDC-48, regulates longevity in Caenorhabditis elegans. Here, we demonstrate that the long-lived cdc-48.1; atx-3 double mutant displays reduced viability under prolonged starvation conditions that can be attributed to the loss of catalytically active ATX-3. Reducing the levels of the autophagy protein BEC-1 sensitized worms to the effect of ATX-3 deficiency, suggesting a role of ATX-3 in autophagy. In support of this conclusion, the depletion of ATXN3 in human cells caused a reduction in autophagosomal degradation of proteins. Surprisingly, reduced degradation in ATXN3-depleted cells coincided with an increase in the number of autophagosomes while levels of lipidated LC3 remained unaffected. We identified two conserved LIR domains in the catalytic Josephin domain of ATXN3 that directly interacted with the autophagy adaptors LC3C and GABARAP in vitro. While ATXN3 localized to early autophagosomes, it was not subject to lysosomal degradation, suggesting a transient regulatory interaction early in the autophagic pathway. We propose that the deubiquitylase ATX-3/ATXN3 stimulates autophagic degradation by preventing superfluous initiation of autophagosomes, thereby promoting an efficient autophagic flux important to survive starvation.

PMID: 31625269 [PubMed - as supplied by publisher]

Heat shock factor 1-mediated transcription activation of Omi/HtrA2 induces myocardial mitochondrial apoptosis in the aging heart.

Aging (Albany NY). 2019 Oct 18;11:

Authors: Liu D, Wu L, Wu Y, Wei X, Wang W, Zhang S, Yi M, Li J, Liu H, Ma X

Abstract
BACKGROUND: Increased cardiac apoptosis is a hallmark of the elderly, which in turn increases the risk for developing cardiac disease. The overexpression of Omi/HtrA2 mRNA and protein contributes to apoptosis in the aged heart. Heat shock factor 1 (HSF1) is a transcription factor that binds to the promoter of Omi/HtrA2 in the aging myocardium. However, whether HSF1 participates in cardiomyocyte apoptosis via transcriptional regulation of Omi/HtrA2 remains unclear. The present study was designed to investigate whether HSF1 plays a role in Omi/HtrA2 transcriptional regulation and myocardial apoptosis.
METHODS AND RESULTS: Assessment of the hearts of mice of different ages was performed, which indicated a decrease in cardiac function reserve and an increase in mitochondrial apoptosis. Omi/HtrA2 overexpression in the elderly was negatively correlated with left ventricular function after exercise overload and positively correlated with myocardial Caspase-9 apoptosis. Chromatin immunoprecipitation (ChIP) of aging hearts and plasmid transfection/RNA interference of H9C2 cells revealed that enhancement of HSF1 expression promotes Omi/HtrA2 expression by inducing the promoter activity of Omi/HtrA2 while also increasing mitochondrial apoptosis by upregulating Omi/HtrA2 expression.
CONCLUSIONS: HSF1 acts as a transcriptional factor that induces Omi/HtrA2 expression and Caspase-9 apoptosis in aged cardiomyocytes, while also decreasing cardiac function reserve.

PMID: 31627188 [PubMed - as supplied by publisher]

Age-dependent relationship between preoperative serum aminotransferase and mortality after cardiovascular surgery.

Aging (Albany NY). 2019 Oct 18;11:

Authors: Nam JS, Kim WJ, An SM, Choi DK, Chin JH, Lee EH, Choi IC

Abstract
Although serum aminotransferase levels are frequently measured for preoperative evaluation, their prognostic value to postoperative outcomes remain unclear. This study aimed to investigate the relationship between preoperative serum aminotransferase levels and postoperative 90-day mortality in patients undergoing cardiovascular surgery. We included adult patients (n=6264) who underwent cardiovascular surgery between January 2010 and December 2016 at a tertiary academic hospital. Preoperative serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), and De Ritis ratio (defined as AST/ALT) were categorized into three groups: low (≤20th percentile), middle (20th-80th percentile), and high (>80th percentile). Of the 6264 patients enrolled (40.4% women; median age, 62 years), 183 (2.9%) died within 90 days postoperatively. Multivariable-adjusted analyses revealed low ALT (hazard ratio 1.58, 95% confidence interval, 1.14-2.18) and high De Ritis ratio (hazard ratio 1.59, 95% confidence interval, 1.15-2.20) were independent predictors of postoperative mortality, but AST did not have a statistically significant association. The association of low ALT and high De Ritis ratio with 90-day mortality was more pronounced in patients older than 60 years (P-values for interaction <0.05). Therefore, preoperative serum aminotransferase levels may be a valuable prognostic marker in patients with cardiovascular surgery, particularly in the elderly.

PMID: 31627189 [PubMed - as supplied by publisher]

Proteostasis collapse is a driver of cell aging and death.

Proc Natl Acad Sci U S A. 2019 Oct 16;:

Authors: Santra M, Dill KA, de Graff AMR

Abstract
What molecular processes drive cell aging and death? Here, we model how proteostasis-i.e., the folding, chaperoning, and maintenance of protein function-collapses with age from slowed translation and cumulative oxidative damage. Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage. The model agrees with experiments in the worm Caenorhabditis elegans that show the following: Life span shortens nonlinearly with increased temperature or added oxidant concentration, and life span increases in mutants having more chaperones or proteasomes. It predicts observed increases in cellular oxidative damage with age and provides a mechanism for the Gompertz-like rise in mortality observed in humans and other organisms. Overall, the model shows how the instability of proteins sets the rate at which damage accumulates with age and upends a cell's normal proteostasis balance.

PMID: 31619571 [PubMed - as supplied by publisher]

Moderation of neural excitation promotes longevity.

Nature. 2019 Oct;574(7778):338-340

Authors: Tavernarakis N

PMID: 31619782 [PubMed - in process]

Regulation of lifespan by neural excitation and REST.

Nature. 2019 Oct;574(7778):359-364

Authors: Zullo JM, Drake D, Aron L, O'Hern P, Dhamne SC, Davidsohn N, Mao CA, Klein WH, Rotenberg A, Bennett DA, Church GM, Colaiácovo MP, Yankner BA

Abstract
The mechanisms that extend lifespan in humans are poorly understood. Here we show that extended longevity in humans is associated with a distinct transcriptome signature in the cerebral cortex that is characterized by downregulation of genes related to neural excitation and synaptic function. In Caenorhabditis elegans, neural excitation increases with age and inhibition of excitation globally, or in glutamatergic or cholinergic neurons, increases longevity. Furthermore, longevity is dynamically regulated by the excitatory-inhibitory balance of neural circuits. The transcription factor REST is upregulated in humans with extended longevity and represses excitation-related genes. Notably, REST-deficient mice exhibit increased cortical activity and neuronal excitability during ageing. Similarly, loss-of-function mutations in the C. elegans REST orthologue genes spr-3 and spr-4 elevate neural excitation and reduce the lifespan of long-lived daf-2 mutants. In wild-type worms, overexpression of spr-4 suppresses excitation and extends lifespan. REST, SPR-3, SPR-4 and reduced excitation activate the longevity-associated transcription factors FOXO1 and DAF-16 in mammals and worms, respectively. These findings reveal a conserved mechanism of ageing that is mediated by neural circuit activity and regulated by REST.

PMID: 31619788 [PubMed - in process]

Population-based neuroimaging reveals traces of childbirth in the maternal brain.

Proc Natl Acad Sci U S A. 2019 Oct 15;:

Authors: de Lange AG, Kaufmann T, van der Meer D, Maglanoc LA, Alnæs D, Moberget T, Douaud G, Andreassen OA, Westlye LT

Abstract
Maternal brain adaptations have been found across pregnancy and postpartum, but little is known about the long-term effects of parity on the maternal brain. Using neuroimaging and machine learning, we investigated structural brain characteristics in 12,021 middle-aged women from the UK Biobank, demonstrating that parous women showed less evidence of brain aging compared to their nulliparous peers. The relationship between childbirths and a "younger-looking" brain could not be explained by common genetic variation or relevant confounders. Although prospective longitudinal studies are needed, the results suggest that parity may involve neural changes that could influence women's brain aging later in life.

PMID: 31615888 [PubMed - as supplied by publisher]

Metabolic stress is a primary pathogenic event in transgenic Caenorhabditis elegans expressing pan-neuronal human amyloid beta.

Elife. 2019 10 15;8:

Authors: Teo E, Ravi S, Barardo D, Kim HS, Fong S, Cazenave-Gassiot A, Tan TY, Ching J, Kovalik JP, Wenk MR, Gunawan R, Moore PK, Halliwell B, Tolwinski N, Gruber J

Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disease affecting the elderly worldwide. Mitochondrial dysfunction has been proposed as a key event in the etiology of AD. We have previously modeled amyloid-beta (Aβ)-induced mitochondrial dysfunction in a transgenic Caenorhabditis elegans strain by expressing human Aβ peptide specifically in neurons (GRU102). Here, we focus on the deeper metabolic changes associated with this Aβ-induced mitochondrial dysfunction. Integrating metabolomics, transcriptomics and computational modeling, we identify alterations in Tricarboxylic Acid (TCA) cycle metabolism following even low-level Aβ expression. In particular, GRU102 showed reduced activity of a rate-limiting TCA cycle enzyme, alpha-ketoglutarate dehydrogenase. These defects were associated with elevation of protein carbonyl content specifically in mitochondria. Importantly, metabolic failure occurred before any significant increase in global protein aggregate was detectable. Treatment with an anti-diabetes drug, Metformin, reversed Aβ-induced metabolic defects, reduced protein aggregation and normalized lifespan of GRU102. Our results point to metabolic dysfunction as an early and causative event in Aβ-induced pathology and a promising target for intervention.

PMID: 31610847 [PubMed - in process]

Redirection of SKN-1 abates the negative metabolic outcomes of a perceived pathogen infection.

Proc Natl Acad Sci U S A. 2019 Oct 14;:

Authors: Nhan JD, Turner CD, Anderson SM, Yen CA, Dalton HM, Cheesman HK, Ruter DL, Uma Naresh N, Haynes CM, Soukas AA, Pukkila-Worley R, Curran SP

Abstract
Early host responses toward pathogens are essential for defense against infection. In Caenorhabditis elegans, the transcription factor, SKN-1, regulates cellular defenses during xenobiotic intoxication and bacterial infection. However, constitutive activation of SKN-1 results in pleiotropic outcomes, including a redistribution of somatic lipids to the germline, which impairs health and shortens lifespan. Here, we show that exposing C. elegans to Pseudomonas aeruginosa similarly drives the rapid depletion of somatic, but not germline, lipid stores. Modulating the epigenetic landscape refines SKN-1 activity away from innate immunity targets, which alleviates negative metabolic outcomes. Similarly, exposure to oxidative stress redirects SKN-1 activity away from pathogen response genes while restoring somatic lipid distribution. In addition, activating p38/MAPK signaling in the absence of pathogens, is sufficient to drive SKN-1-dependent loss of somatic fat. These data define a SKN-1- and p38-dependent axis for coordinating pathogen responses, lipid homeostasis, and survival and identify transcriptional redirection, rather than inactivation, as a mechanism for counteracting the pleiotropic consequences of aberrant transcriptional activity.

PMID: 31611372 [PubMed - as supplied by publisher]

The PedBE clock accurately estimates DNA methylation age in pediatric buccal cells.

Proc Natl Acad Sci U S A. 2019 Oct 14;:

Authors: McEwen LM, O'Donnell KJ, McGill MG, Edgar RD, Jones MJ, MacIsaac JL, Lin DTS, Ramadori K, Morin A, Gladish N, Garg E, Unternaehrer E, Pokhvisneva I, Karnani N, Kee MZL, Klengel T, Adler NE, Barr RG, Letourneau N, Giesbrecht GF, Reynolds JN, Czamara D, Armstrong JM, Essex MJ, de Weerth C, Beijers R, Tollenaar MS, Bradley B, Jovanovic T, Ressler KJ, Steiner M, Entringer S, Wadhwa PD, Buss C, Bush NR, Binder EB, Boyce WT, Meaney MJ, Horvath S, Kobor MS

Abstract
The development of biological markers of aging has primarily focused on adult samples. Epigenetic clocks are a promising tool for measuring biological age that show impressive accuracy across most tissues and age ranges. In adults, deviations from the DNA methylation (DNAm) age prediction are correlated with several age-related phenotypes, such as mortality and frailty. In children, however, fewer such associations have been made, possibly because DNAm changes are more dynamic in pediatric populations as compared to adults. To address this gap, we aimed to develop a highly accurate, noninvasive, biological measure of age specific to pediatric samples using buccal epithelial cell DNAm. We gathered 1,721 genome-wide DNAm profiles from 11 different cohorts of typically developing individuals aged 0 to 20 y old. Elastic net penalized regression was used to select 94 CpG sites from a training dataset (n = 1,032), with performance assessed in a separate test dataset (n = 689). DNAm at these 94 CpG sites was highly predictive of age in the test cohort (median absolute error = 0.35 y). The Pediatric-Buccal-Epigenetic (PedBE) clock was characterized in additional cohorts, showcasing the accuracy in longitudinal data, the performance in nonbuccal tissues and adult age ranges, and the association with obstetric outcomes. The PedBE tool for measuring biological age in children might help in understanding the environmental and contextual factors that shape the DNA methylome during child development, and how it, in turn, might relate to child health and disease.

PMID: 31611402 [PubMed - as supplied by publisher]

Decreased levels of circulating trimethylamine N-oxide alleviate cognitive and pathological deterioration in transgenic mice: a potential therapeutic approach for Alzheimer's disease.

Aging (Albany NY). 2019 Oct 14;11:

Authors: Gao Q, Wang Y, Wang X, Fu S, Zhang X, Wang RT, Zhang X

Abstract
Trimethylamine-N-oxide (TMAO), a metabolite of gut microbiota, has been implicated in the pathogenesis of Alzheimer's disease (AD). However, the mechanisms by which TMAO influence cognitive and pathological processes in the AD have not been investigated. In this study, we found that the circulating TMAO levels displayed an age-related increase in both WT and APP/PS1 mice and association with AD-like behavioral and pathological profile. Reduced TMAO by 3,3-Dimethyl-1-butanol (DMB) treatment ameliorated the cognitive deterioration and long-term potentiation (LTP) in APP/PS1 mice. Moreover, DMB treatment also induced a decrease in the Amyloid-β (Aβ)1-42, β-secretase, and β-secretase-cleaved C-terminal fragment (βCTF) levels in the hippocampus. Finally, the effects obtained after treatment with DMB were accompanied by a reduction in circulating clusterin levels and hippocampal neuroinflammatory status in APP/PS1 mice. These findings demonstrate that elevated circulating TMAO during the aging process might deteriorate cognitive function and pathology in APP/PS1 mice.

PMID: 31612864 [PubMed - as supplied by publisher]

Transcriptome signature of cellular senescence.

Nucleic Acids Res. 2019 Oct 15;:

Authors: Casella G, Munk R, Kim KM, Piao Y, De S, Abdelmohsen K, Gorospe M

PMID: 31612919 [PubMed - as supplied by publisher]

Granulovacuolar degeneration bodies: Red alert for neurons with MAPT/tau pathology.

Autophagy. 2019 Oct 15;:

Authors: Wiersma VI, Scheper W

Abstract
In Alzheimer disease patients, MAPT/tau pathology and granulovacuolar degeneration bodies (GVBs) co-occur in the same brain regions and in the same cells. The interdependence of these neuropathological hallmarks and the identity of GVBs have long been elusive. Recently, we showed that MAPT pathology causes GVB formation in neurons in vivo and in vitro. Using these novel GVB models, we identified GVBs as lysosomal structures at the convergence of the endo- and autolysosomal pathways. Here, the possible functional consequences of neuronal GVB formation are discussed.

PMID: 31613164 [PubMed - as supplied by publisher]

Frailty: implications for clinical practice and public health.

Lancet. 2019 Oct 12;394(10206):1365-1375

Authors: Hoogendijk EO, Afilalo J, Ensrud KE, Kowal P, Onder G, Fried LP

Abstract
Frailty is an emerging global health burden, with major implications for clinical practice and public health. The prevalence of frailty is expected to rise alongside rapid growth in the ageing population. The course of frailty is characterised by a decline in functioning across multiple physiological systems, accompanied by an increased vulnerability to stressors. Having frailty places a person at increased risk of adverse outcomes, including falls, hospitalisation, and mortality. Studies have shown a clear pattern of increased health-care costs and use associated with frailty. All older adults are at risk of developing frailty, although risk levels are substantially higher among those with comorbidities, low socioeconomic position, poor diet, and sedentary lifestyles. Lifestyle and clinical risk factors are potentially modifiable by specific interventions and preventive actions. The concept of frailty is increasingly being used in primary, acute, and specialist care. However, despite efforts over the past three decades, agreement on a standard instrument to identify frailty has not yet been achieved. In this Series paper, we provide an overview of the global impact and burden of frailty, the usefulness of the frailty concept in clinical practice, potential targets for frailty prevention, and directions that need to be explored in the future.

PMID: 31609228 [PubMed - in process]

Conserved aging-related signatures of senescence and inflammation in different tissues and species.

Aging (Albany NY). 2019 Oct 12;11:

Authors: Barth E, Srivastava A, Stojiljkovic M, Frahm C, Axer H, Witte OW, Marz M

Abstract
Increasing evidence indicates that chronic inflammation and senescence are the cause of many severe age-related diseases, with both biological processes highly upregulated during aging. However, until now, it has remained unknown whether specific inflammation- or senescence-related genes exist that are common between different species or tissues. These potential markers of aging could help to identify possible targets for therapeutic interventions of aging-associated afflictions and might also deepen our understanding of the principal mechanisms of aging. With the objective of identifying such signatures of aging and tissue-specific aging markers, we analyzed a multitude of cross-sectional RNA-Seq data from four evolutionarily distinct species (human, mouse and two fish) and four different tissues (blood, brain, liver and skin). In at least three different species and three different tissues, we identified several genes that displayed similar expression patterns that might serve as potential aging markers. Additionally, we show that genes involved in aging-related processes tend to be tighter controlled in long-lived than in average-lived individuals. These observations hint at a general genetic level that affect an individual's life span. Altogether, this descriptive study contributes to a better understanding of common aging signatures as well as tissue-specific aging patterns and supplies the basis for further investigative age-related studies.

PMID: 31606727 [PubMed - as supplied by publisher]

Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long-lived and cancer-resistant subterranean wild rodent, Spalax.

Aging Cell. 2019 Oct 11;:e13045

Authors: Odeh A, Dronina M, Domankevich V, Shams I, Manov I

Abstract
The blind mole rat (Spalax) is a wild, long-lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence-associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide-induced senescence (EIS), evidenced by an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well-known SASP factors: interleukin-6 (IL6), IL8, IL1α, growth-related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM-1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro-inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA-MB-231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF-κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory-related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age-related chronic inflammation supporting healthy aging and longevity.

PMID: 31605433 [PubMed - as supplied by publisher]

A Nutrition-Longevity Tradeoff Enforced by Innate Immunity.

Mol Cell. 2019 06 06;74(5):864-865

Authors: Wani KA, Goswamy D, Irazoqui JE

Abstract
Dietary restriction (DR) extends lifespan in multiple animal species, but the underlying molecular mechanisms remain poorly understood. A recent study published in Cell Metabolism by Wu et al. (2019) shows that DR represses an evolutionarily conserved p38 MAPK pathway involved in innate immunity, leading to diminished expression of p38 MAPK-regulated genes and extended lifespan.

PMID: 31173721 [PubMed - indexed for MEDLINE]

An aging phenotype in the wild.

Science. 2019 09 20;365(6459):1244-1245

Authors: Gaillard JM, Lemaître JF

PMID: 31604224 [PubMed - indexed for MEDLINE]