Aging, Lifespan & Longevity

An excreted small molecule promotes C. elegans reproductive development and aging.

Nat Chem Biol. 2019 Aug;15(8):838-845

Authors: Ludewig AH, Artyukhin AB, Aprison EZ, Rodrigues PR, Pulido DC, Burkhardt RN, Panda O, Zhang YK, Gudibanda P, Ruvinsky I, Schroeder FC

Abstract
Excreted small-molecule signals can bias developmental trajectories and physiology in diverse animal species. However, the chemical identity of these signals remains largely obscure. Here we report identification of an unusual N-acylated glutamine derivative, nacq#1, that accelerates reproductive development and shortens lifespan in Caenorhabditis elegans. Produced predominantly by C. elegans males, nacq#1 hastens onset of sexual maturity in hermaphrodites by promoting exit from the larval dauer diapause and by accelerating late larval development. Even at picomolar concentrations, nacq#1 shortens hermaphrodite lifespan, suggesting a trade-off between reproductive investment and longevity. Acceleration of development by nacq#1 requires chemosensation and is dependent on three homologs of vertebrate steroid hormone receptors. Unlike ascaroside pheromones, which are restricted to nematodes, fatty acylated amino acid derivatives similar to nacq#1 have been reported from humans and invertebrates, suggesting that related compounds may serve signaling functions throughout metazoa.

PMID: 31320757 [PubMed - in process]

Optimism is not associated with two indicators of DNA methylation aging.

Aging (Albany NY). 2019 Jul 18;:

Authors: Kim ES, Fong K, Lee L, Spiro A, Schwartz J, Whitsel E, Horvath S, Wang C, Hou L, Baccarelli AA, Li Y, Stewart J, Manson JE, Grodstein F, DeMeo DL, Kubzansky LD

Abstract
Evidence indicates associations between higher optimism and reduced risk of age-related conditions and premature mortality. This suggests optimism is a positive health asset, but research identifying potential biological mechanisms underlying these associations remains limited. One potential pathway is slower cellular aging, which may delay age-related deterioration in health. Data were from the Women's Health Initiative (WHI) (N=3,298) and the Veterans Affairs Normative Aging Study (NAS) (N=514), and included dispositional and explanatory style optimism measures. We evaluated whether higher optimism was associated with metrics suggestive of less cellular aging, as indicated by two DNA methylation algorithms, intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA); these algorithms represent accelerated biologic aging that exceeds chronological age. We used linear regression models to test our hypothesis while considering several covariates (sociodemographics, depressive symptoms, health behaviors). In both cohorts, we found consistently null associations of all measures of optimism with both measures of DNA methylation aging, regardless of covariates considered. For example, in fully-adjusted models, dispositional optimism was not associated with either IEAA (WHI:β=0.02; 95% Confidence Interval [CI]:-0.15-0.20; NAS:β=-0.06; 95% CI:-0.56-0.44) or EEAA (WHI:β=-0.04; 95% CI: -0.26-0.17; NAS:β=-0.17; 95% CI: -0.80-0.46). Higher optimism was not associated with reduced cellular aging as measured in this study.

PMID: 31322503 [PubMed - as supplied by publisher]

Comparative studies of mitochondrial reactive oxygen species in animal longevity: Technical pitfalls and possibilities.

Aging Cell. 2019 Jul 19;:e13009

Authors: Munro D, Pamenter ME

Abstract
The mitochondrial oxidative theory of aging has been repeatedly investigated over the past 30 years by comparing the efflux of hydrogen peroxide (H2 O2 ) from isolated mitochondria of long- and short-lived species using horseradish peroxidase-based assays. However, a clear consensus regarding the relationship between H2 O2 production rates and longevity has not emerged. Concomitantly, novel insights into the mechanisms of reactive oxygen species (ROS) handling by mitochondria themselves should have raised concerns about the validity of this experimental approach. Here, we review pitfalls of the horseradish peroxidase/amplex red detection system for the measurement of mitochondrial ROS formation rates, with an emphasis on longevity studies. Importantly, antioxidant systems in the mitochondrial matrix are often capable of scavenging H2 O2 faster than mitochondria produce it. As a consequence, as much as 84% of the H2 O2 produced by mitochondria may be consumed before it diffuses into the reaction medium, where it can be detected by the horseradish peroxidase/amplex red system, this proportion is likely not consistent across species. Furthermore, previous studies often used substrates that elicit H2 O2 formation at a much higher rate than in physiological conditions and at sites of secondary importance in vivo. Recent evidence suggests that the activity of matrix antioxidants may correlate with longevity instead of the rate of H2 O2 formation. We conclude that past studies have been methodologically insufficient to address the putative relationship between longevity and mitochondrial ROS. Thus, novel methodological approaches are required that more accurately encompass mitochondrial ROS metabolism.

PMID: 31322803 [PubMed - as supplied by publisher]

Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.

Aging Cell. 2019 Jul 18;:e13004

Authors: Miao J, Liu J, Niu J, Zhang Y, Shen W, Luo C, Liu Y, Li C, Li H, Yang P, Liu Y, Hou FF, Zhou L

Abstract
Renal fibrosis is the common pathological feature in a variety of chronic kidney diseases. Aging is highly associated with the progression of renal fibrosis. Among several determinants, mitochondrial dysfunction plays an important role in aging. However, the underlying mechanisms of mitochondrial dysfunction in age-related renal fibrosis are not elucidated. Herein, we found that Wnt/β-catenin signaling and renin-angiotensin system (RAS) activity were upregulated in aging kidneys. Concomitantly, mitochondrial mass and functions were impaired with aging. Ectopic expression of Klotho, an antagonist of endogenous Wnt/β-catenin activity, abolished renal fibrosis in d-galactose (d-gal)-induced accelerated aging mouse model and significantly protected renal mitochondrial functions by preserving mass and diminishing the production of reactive oxygen species. In an established aging mouse model, dickkopf 1, a more specific Wnt inhibitor, and the mitochondria-targeted antioxidant mitoquinone restored mitochondrial mass and attenuated tubular senescence and renal fibrosis. In a human proximal tubular cell line (HKC-8), ectopic expression of Wnt1 decreased biogenesis and induced dysfunction of mitochondria, and triggered cellular senescence. Moreover, d-gal triggered the transduction of Wnt/β-catenin signaling, which further activated angiotensin type 1 receptor (AT1), and then decreased the mitochondrial mass and increased cellular senescence in HKC-8 cells and primary cultured renal tubular cells. These effects were inhibited by AT1 blocker of losartan. These results suggest inhibition of Wnt/β-catenin signaling and the RAS could slow the onset of age-related mitochondrial dysfunction and renal fibrosis. Taken together, our results indicate that Wnt/β-catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction.

PMID: 31318148 [PubMed - as supplied by publisher]

Osteoprotegerin as a biomarker of geriatric frailty syndrome.

Aging (Albany NY). 2019 Jul 17;:

Authors: Valentini A, Cianfarani MA, Tarantino U, Di Daniele N, Bertoli A

Abstract
The lack of a univocal definition of frailty, a condition frequently found in the elderly population which is correlated with an increased risk of mortality, has prompted the search for clinical and laboratory parameters associated with this condition. Whereas OPG is a protein involved in different pathophysiological conditions including bone, vascular, immune and tumor disease and studies found a positive linear correlation between OPG and age we hypothesized that it may represent a frailty marker in the elderly.We conducted an observational study of 172 elderly subjects, with and without hip fracture, including a multidimensional geriatric evaluation and a laboratory evaluation, aimed to evaluate the association between OPG and frailty.Frailty Score was associated with FT3 and osteoprotegerin (OPG), regardless of fracture event. Excluding subjects with hip fracture, in whom the acute event had a direct effect on bone production of OPG, the Frailty Score showed a linear correlation with circulating levels of osteoprotegerin.In the elderly, an increase in osteoprotegerin levels may reflect a progressive accumulation of organ damage leading to the development of frailty. The correlation between OPG and Frailty Score found in our study points to its potential use as a biomarker for geriatric frailty syndrome.

PMID: 31311890 [PubMed - as supplied by publisher]

Hsp90β interacts with MDM2 to suppress p53-dependent senescence during skeletal muscle regeneration.

Aging Cell. 2019 Jul 17;:e13003

Authors: He MY, Xu SB, Qu ZH, Guo YM, Liu XC, Cong XX, Wang JF, Low BC, Li L, Wu Q, Lin P, Yan SG, Bao Z, Zhou YT, Zheng LL

Abstract
Cellular senescence plays both beneficial and detrimental roles in embryonic development and tissue regeneration, while the underlying mechanism remains elusive. Recent studies disclosed the emerging roles of heat-shock proteins in regulating muscle regeneration and homeostasis. Here, we found that Hsp90β, but not Hsp90α isoform, was significantly upregulated during muscle regeneration. RNA-seq analysis disclosed a transcriptional elevation of p21 in Hsp90β-depleted myoblasts, which is due to the upregulation of p53. Moreover, knockdown of Hsp90β in myoblasts resulted in p53-dependent cellular senescence. In contrast to the notion that Hsp90 interacts with and protects mutant p53 in cancer, Hsp90β preferentially bound to wild-type p53 and modulated its degradation via a proteasome-dependent manner. Moreover, Hsp90β interacted with MDM2, the chief E3 ligase of p53, to regulate the stability of p53. In line with these in vitro studies, the expression level of p53-p21 axis was negatively correlated with Hsp90β in aged mice muscle. Consistently, administration of 17-AAG, a Hsp90 inhibitor under clinical trial, impaired muscle regeneration by enhancing injury-induced senescence in vivo. Taken together, our finding revealed a previously unappreciated role of Hsp90β in regulating p53 stability to suppress senescence both in vitro and in vivo.

PMID: 31313490 [PubMed - as supplied by publisher]

PGC-1α, a potential therapeutic target against kidney aging.

Aging Cell. 2019 Jul 16;:e12994

Authors: Lee G, Uddin MJ, Kim Y, Ko M, Yu I, Ha H

Abstract
Aging is defined as changes in an organism over time. The proportion of the aged population is markedly increasing worldwide. The kidney, as an essential organ with a high energy requirement, is one of the most susceptible organs to aging. It is involved in glucose metabolism via gluconeogenesis, glucose filtration and reabsorption, and glucose utilization. Proximal tubular epithelial cells (PTECs) depend on lipid metabolism to meet the high demand for ATP. Recent studies have shown that aging-related kidney dysfunction is highly associated with metabolic changes in the kidney. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional coactivator, plays a major role in the regulation of mitochondrial biogenesis, peroxisomal biogenesis, and glucose and lipid metabolism. PGC-1α is abundant in tissues, including kidney PTECs, which demand high energy. Many in vitro and in vivo studies have demonstrated that the activation of PGC-1α by genetic or pharmacological intervention prevents telomere shortening and aging-related changes in the skeletal muscle, heart, and brain. The activation of PGC-1α can also prevent kidney dysfunction in various kidney diseases. Therefore, a better understanding of the effect of PGC-1α activation in various organs on aging and kidney diseases may unveil a potential therapeutic strategy against kidney aging.

PMID: 31313501 [PubMed - as supplied by publisher]

Suppressing the dark side of autophagy.

Autophagy. 2019 Jul 17;:

Authors: Zhou B, Soukas AA

Abstract
A wide variety of genetic, pharmacological and nutrient manipulations that extend lifespan in model organisms do so in a manner dependent upon increased autophagic flux. However, our recent findings suggest that when mitochondrial membrane integrity is compromised, macroautophagy/autophagy can be detrimental. In C. elegans lacking the serine/threonine kinase mechanistic target of rapamycin kinase complex 2 and its downstream effector SGK-1 (Serum- and Glucocorticoid-inducible Kinase homolog), lifespan is shortened in spite of increased levels of autophagy, whereas reducing autophagy restores normal lifespan. This is due to a concomitant defect in mitochondrial permeability in mutants defective in either SGK-1 or mechanistic target of rapamycin kinase complex 2, attributable to increased VDAC-1 (VDAC Voltage Dependent Anion Channel homolog) protein level. More generally, we find that induction of mitochondrial permeability reverses each and every tested paradigm of autophagy-dependent lifespan extension and, further, exacerbates ischemia-reperfusion injury. In this punctum, we discuss our finding that autophagy with increased mitochondrial permeability is a detrimental combination conserved from nematode to mammals.

PMID: 31313620 [PubMed - as supplied by publisher]

The positive impacts of early-life education on cognition, leisure activity, and brain structure in healthy aging.

Aging (Albany NY). 2019 Jul 17;11:

Authors: Chen Y, Lv C, Li X, Zhang J, Chen K, Liu Z, Li H, Fan J, Qin T, Luo L, Zhang Z

Abstract
Education in people's early lives are positively related to their cognitive function, but its modulating effects on detailed cognition domains, its interaction with leisure activities and the associated brain changes have yet to be investigated. This report used data from 659 cognitively normal community dwelling elderly who completed neuropsychological tests, leisure activities measurement, and 78 of them underwent structural and diffusion MRI scans. We found that: (i) the highly educated elderly had a better cognitive functioning in multi-domains, higher frequencies of participation in knowledge-related leisure activities, and slower age-related reductions of executive function; (ii) the intellectual and social types of leisure activities mediated the association between education and multiple cognitive domains, including memory, language, attention and executive function; (iii) there was a significant age by education interaction on the gray matter volume of the anterior brain regions and white matter integrity; and (iv) the interaction between age and education affected cognition indirectly through white matter integrity analyzed using structural equation model. Overall, our results revealed that high education in early life served as a protective factor in aging that may help to postpone cognitive and brain reserve decline in cognitively normal aging.

PMID: 31315089 [PubMed - as supplied by publisher]

Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia.

Mol Cell Biol. 2019 Jul 15;:

Authors: Joseph GA, Wang S, Jacobs CE, Zhou W, Kimble GC, Tse HW, Eash JK, Shavlakadze T, Glass DJ

Abstract
There is a lack of pharmacological interventions available for sarcopenia, a progressive age-associated loss of muscle mass, leading to a decline in mobility and quality of life. We found mTORC1 (mammalian target of rapamycin complex 1), a well-established positive modulator of muscle mass, to be surprisingly hyperactivated in sarcopenic muscle. Furthermore, inhibition of the mTORC1 pathway counteracted sarcopenia, as determined by observing an increase in muscle mass and fiber type cross sectional area in select muscle groups, again surprising because mTORC1 signaling has been shown to be required for skeletal muscle mass gains in some models of hypertrophy. Additionally, several genes related to senescence were downregulated while gene expression indicators of neuromuscular junction denervation were diminished using a low dose of a rapalog. Therefore partial mTORC1 inhibition may delay the progression of sarcopenia by directly and indirectly modulating multiple age-associated pathways, implicating mTORC1 as a therapeutic target to treat sarcopenia.

PMID: 31308131 [PubMed - as supplied by publisher]

New label-free automated survival assays reveal unexpected stress resistance patterns during C. elegans aging.

Aging Cell. 2019 Jul 16;:e12998

Authors: Benedetto A, Bambade T, Au C, Tullet JMA, Monkhouse J, Dang H, Cetnar K, Cabreiro F, Chan B, Gems D

Abstract
Caenorhabditis elegans is an excellent model for high-throughput experimental approaches but lacks an automated means to pinpoint time of death during survival assays over a short time frame, that is, easy to implement, highly scalable, robust, and versatile. Here, we describe an automated, label-free, high-throughput method using death-associated fluorescence to monitor nematode population survival (dubbed LFASS for label-free automated survival scoring), which we apply to severe stress and infection resistance assays. We demonstrate its use to define correlations between age, longevity, and severe stress resistance, and its applicability to parasitic nematodes. The use of LFASS to assess the effects of aging on susceptibility to severe stress revealed an unexpected increase in stress resistance with advancing age, which was largely autophagy-dependent. Correlation analysis further revealed that while severe thermal stress resistance positively correlates with lifespan, severe oxidative stress resistance does not. This supports the view that temperature-sensitive protein-handling processes more than redox homeostasis underpin aging in C. elegans. That the ages of peak resistance to infection, severe oxidative stress, heat shock, and milder stressors differ markedly suggests that stress resistance and health span do not show a simple correspondence in C. elegans.

PMID: 31309734 [PubMed - as supplied by publisher]

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons.

Elife. 2019 Jul 16;8:

Authors: Stavoe AK, Gopal PP, Gubas A, Tooze SA, Holzbaur EL

Abstract
Autophagy defects are implicated in multiple late-onset neurodegenerative diseases including Amyotrophic Lateral Sclerosis (ALS) and Alzheimer's, Huntington's, and Parkinson's diseases. Since aging is the most common shared risk factor in neurodegeneration, we assessed rates of autophagy in mammalian neurons during aging. We identified a significant decrease in the rate of constitutive autophagosome biogenesis during aging and observed pronounced morphological defects in autophagosomes in neurons from aged mice. While early stages of autophagosome formation were unaffected, we detected the frequent production of stalled LC3B-negative isolation membranes in neurons from aged mice. These stalled structures recruited the majority of the autophagy machinery, but failed to develop into LC3B-positive autophagosomes. Importantly, ectopically expressing WIPI2B effectively restored autophagosome biogenesis in aged neurons. This rescue is dependent on the phosphorylation state of WIPI2B at the isolation membrane, suggesting a novel therapeutic target in age-associated neurodegeneration.

PMID: 31309927 [PubMed - in process]

The transcription factor Hey and nuclear lamins specify and maintain cell identity.

Elife. 2019 Jul 16;8:

Authors: Flint Brodsly N, Bitman-Lotan E, Boico O, Shafat A, Monastirioti M, Gessler M, Delidakis C, Rincon-Arano H, Orian A

Abstract
The inability of differentiated cells to maintain their identity is a hallmark of age-related diseases. We found that the transcription factor Hey supervises the identity of differentiated enterocytes (ECs) in the adult Drosophila midgut. Lineage tracing established that Hey-deficient ECs are unable to maintain their unique nuclear organization and identity. To supervise cell identity, Hey determines the expression of nuclear lamins, switching from a stem-cell lamin configuration to a differentiated lamin configuration. Moreover, continued Hey expression is required to conserve large-scale nuclear organization. During aging, Hey levels decline, and EC identity and gut homeostasis are impaired, including pathological reprograming and compromised gut integrity. These phenotypes are highly similar to those observed upon acute targeting of Hey or perturbation of lamin expression in ECs in young adults. Indeed, aging phenotypes were suppressed by continued expression of Hey in ECs, suggesting that a Hey-lamin network safeguards nuclear organization and differentiated cell identity.

PMID: 31310235 [PubMed - in process]

Changes in presynaptic calcium signalling accompany age-related deficits in hippocampal LTP and cognitive impairment.

Aging Cell. 2019 Jul 16;:e13008

Authors: Pereda D, Al-Osta I, Okorocha AE, Easton A, Hartell NA

Abstract
The loss of cognitive function accompanying healthy aging is not associated with extensive or characteristic patterns of cell death, suggesting it is caused by more subtle changes in synaptic properties. In the hippocampal CA1 region, long-term potentiation requires stronger stimulation for induction in aged rats and mice and long-term depression becomes more prevalent. An age-dependent impairment of postsynaptic calcium homeostasis may underpin these effects. We have examined changes in presynaptic calcium signalling in aged mice using a transgenic mouse line (SyG37) that expresses a genetically encoded calcium sensor in presynaptic terminals. SyG37 mice showed an age-dependent decline in cognitive abilities in behavioural tasks that require hippocampal processing including the Barnes maze, T-maze and object location but not recognition tests. The incidence of LTP was significantly impaired in animals over 18 months of age. These effects of aging were accompanied by a persistent increase in resting presynaptic calcium, an increase in the presynaptic calcium signal following Schaffer collateral fibre stimulation, an increase in postsynaptic fEPSP slope and a reduction in paired-pulse facilitation. These effects were not caused by synapse proliferation and were of presynaptic origin since they were evident in single presynaptic boutons. Aged synapses behaved like younger ones when the extracellular calcium concentration was reduced. Raising extracellular calcium had little effect on aged synapses but altered the properties of young synapses into those of their aged counterparts. These effects can be readily explained by an age-dependent change in the properties or numbers of presynaptic calcium channels.

PMID: 31310431 [PubMed - as supplied by publisher]

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging.

Cell Stem Cell. 2019 Jul 04;:

Authors: Ho YH, Del Toro R, Rivera-Torres J, Rak J, Korn C, García-García A, Macías D, González-Gómez C, Del Monte A, Wittner M, Waller AK, Foster HR, López-Otín C, Johnson RS, Nerlov C, Ghevaert C, Vainchenker W, Louache F, Andrés V, Méndez-Ferrer S

Abstract
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β2-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β3-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β3-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.

PMID: 31303548 [PubMed - as supplied by publisher]

Targeting HMGB1 by ethyl pyruvate ameliorates systemic lupus erythematosus and reverses the senescent phenotype of bone marrow-mesenchymal stem cells.

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

Authors: Ji J, Fu T, Dong C, Zhu W, Yang J, Kong X, Zhang Z, Bao Y, Zhao R, Ge X, Sha X, Lu Z, Li J, Gu Z

Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple organs and systems. Mesenchymal stem cells (MSCs) from SLE patients have demonstrated defects such as impaired growth, senescence phenotype and immunomodulatory functions. Some studies have suggested the close connection between inflammation microenvironment and cellular senescence. In the current study, we detected cytokines levels in bone marrow supernatant by the quantitative proteomics analysis, and found the expression of HMGB1 was remarkably increased in bone marrow from SLE patients. Senescence associated-β-galactosidase (SA-β-gal) staining, F-actin staining and flow cytometry were used to detect the senescence of cells. After stimulation of HMGB1 in normal MSCs, the ratio of SA-β-gal positive in BM-MSCs was increased, the organization of cytoskeleton was disordered, and TLR4-NF-κB signaling was activated. Finally, Ethyl pyruvate (EP) (40 mg/kg and 100 mg/kg, three times a week), a high security HMGB1 inhibitor, was injected intraperitoneally to treat MRL/lpr mice for 8 weeks. We demonstrated that EP alleviated the clinical aspects of lupus nephritis and prolonged survival of MRL/lpr mice. In the meantime, EP reversed the senescent phenotype of BM-MSCs from MRL/lpr mice. HMGB1 could be a promising target in SLE patients, and might be one of the reasons of recurrence after MSCs transplantation.

PMID: 31303606 [PubMed - as supplied by publisher]

Enhanced nuclear protein export in premature aging and rescue of the progeria phenotype by modulation of CRM1 activity.

Aging Cell. 2019 Jul 15;:e13002

Authors: García-Aguirre I, Alamillo-Iniesta A, Rodríguez-Pérez R, Vélez-Aguilera G, Amaro-Encarnación E, Jiménez-Gutiérrez E, Vásquez-Limeta A, Samuel Laredo-Cisneros M, Morales-Lázaro SL, Tiburcio-Félix R, Ortega A, Magaña JJ, Winder SJ, Cisneros B

Abstract
The study of Hutchinson-Gilford progeria syndrome (HGPS) has provided important clues to decipher mechanisms underlying aging. Progerin, a mutant lamin A, disrupts nuclear envelope structure/function, with further impairment of multiple processes that culminate in senescence. Here, we demonstrate that the nuclear protein export pathway is exacerbated in HGPS, due to progerin-driven overexpression of CRM1, thereby disturbing nucleocytoplasmic partitioning of CRM1-target proteins. Enhanced nuclear export is central in HGPS, since pharmacological inhibition of CRM1 alleviates all aging hallmarks analyzed, including senescent cellular morphology, lamin B1 downregulation, loss of heterochromatin, nuclear morphology defects, and expanded nucleoli. Exogenous overexpression of CRM1 on the other hand recapitulates the HGPS cellular phenotype in normal fibroblasts. CRM1 levels/activity increases with age in fibroblasts from healthy donors, indicating that altered nuclear export is a common hallmark of pathological and physiological aging. Collectively, our findings provide novel insights into HGPS pathophysiology, identifying CRM1 as potential therapeutic target in HGPS.

PMID: 31305018 [PubMed - as supplied by publisher]

Adult spinal deformity.

Lancet. 2019 Jul 13;394(10193):160-172

Authors: Diebo BG, Shah NV, Boachie-Adjei O, Zhu F, Rothenfluh DA, Paulino CB, Schwab FJ, Lafage V

Abstract
Adult spinal deformity affects the thoracic or thoracolumbar spine throughout the ageing process. Although adolescent spinal deformities taken into adulthood are not uncommon, the most usual causes of spinal deformity in adults are iatrogenic flatback and degenerative scoliosis. Given its prevalence in the expanding portion of the global population aged older than 65 years, the disorder is of growing interest in health care. Physical examination, with a focus on gait and posture, along with radiographical assessment are primarily used and integrated with risk stratification indices to establish optimal treatment planning. Although non-operative treatment is regarded as the first-line response, surgical outcomes are considerably favourable. Global disparities exist in both the assessment and treatment of adults with spinal deformity across countries of varying incomes, which represents an area requiring further investigation. This Seminar presents evidence and knowledge that represent the evolution of data related to spinal deformity in adults over the past several decades.

PMID: 31305254 [PubMed - in process]

Age-associated changes of the intrinsic nervous system in relation with interstitial cells in the pre-weaning goat rumen.

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

Authors: Liang Y, Tarique I, Vistro WA, Liu Y, Wang Z, Haseeb A, Gandahi NS, Iqbal A, Wang S, An T, Yang H, Chen Q, Yang P

Abstract
In this study, we investigated the neural changes and their relationships with interstitial cells (ICs) in the rumen of pre-weaning goats by transmission electron microscopy, western blot and immunofluorescence (antibody: general neuronal marker-Protein Gene Product (PGP9.5)/ IC marker-vimentin). The immunofluorescence results showed that PGP9.5-positive reaction was widely distributed in neuronal soma (NS) and nerve fibre (NF). The NSs were observed in the ganglia of the myenteric plexus (MP) but not in the submucosal plexus. The mean optical density (MOD) of the whole of PGP9.5-positive nerves and the protein expression level of PGP.5 in the rumen wall both decreased significantly with age. However an obvious increase MOD of PGP.5-positive NFs within the rumen epithelium were observed. In the MP, the nerves and ICs were interwoven to form two complex networks that gradually tightened with age. Furthermore, NSs and nerve trunks were surrounded by a ring-boundary layer consisting of several ICs that became physically closer with aging. Moreover, ICs were located nearby NFs within the ML, forming connections between ICs, smooth muscle cells and axons. This study describes the pattern of neural distribution and its association with ICs in the developing rumen which shed light on the postpartum development of ruminants.

PMID: 31305258 [PubMed - as supplied by publisher]

Genome-wide association and evolutionary analyses reveal the formation of swine facial wrinkles in Chinese Erhualian pigs.

Aging (Albany NY). 2019 Jul 15;11:

Authors: Huang T, Zhang M, Yan G, Huang X, Chen H, Zhou L, Deng W, Zhang Z, Qiu H, Ai H, Huang L

Abstract
Wrinkles are uneven concave-convex folds, ridges or creases in skin. Facial wrinkles appear in head, typically increasing along with aging. However in several Chinese indigenous pigs, such as Erhualian pigs, rich facial wrinkles have been generated during the growth stages as one of their breed characteristics. To investigate the genetic basis underlying the development of swine facial wrinkles, we estimated the folding extent of facial wrinkles in a herd of Erhualian pigs (n=332), and then conducted genome-wide association studies and multi-trait meta-analysis for facial wrinkles using 60K porcine chips. We found that facial wrinkles had high heritability estimates of ~0.7 in Erhualian pigs. Notably, only one genome-wide significant QTL was detected at 34.8 Mb on porcine chromosome 7. The most significant SNP rs80983858 located at the 3255-bp downstream of candidate gene GRM4, and the G allele was of benefit to increase facial wrinkles. Evolutionary and selection analyses suggested that the haplotypes containing G allele were under artificial selection, which was consistent with local animal sacrificial custom praying for longevity. Our findings made important clues for further deciphering the molecular mechanism of swine facial wrinkles formation, and shed light on the research of skin wrinkle development in human or other mammals.

PMID: 31306098 [PubMed - as supplied by publisher]