Showing papers in "Biogerontology in 2021"

Aging and age-related diseases: from mechanisms to therapeutic strategies

Abstract: Aging is a physiological process mediated by numerous biological and genetic pathways, which are directly linked to lifespan and are a driving force for all age-related diseases. Human life expectancy has greatly increased in the past few decades, but this has not been accompanied by a similar increase in their healthspan. At present, research on aging biology has focused on elucidating the biochemical and genetic pathways that contribute to aging over time. Several aging mechanisms have been identified, primarily including genomic instability, telomere shortening, and cellular senescence. Aging is a driving factor of various age-related diseases, including neurodegenerative diseases, cardiovascular diseases, cancer, immune system disorders, and musculoskeletal disorders. Efforts to find drugs that improve the healthspan by targeting the pathogenesis of aging have now become a hot topic in this field. In the present review, the status of aging research and the development of potential drugs for aging-related diseases, such as metformin, rapamycin, resveratrol, senolytics, as well as caloric restriction, are summarized. The feasibility, side effects, and future potential of these treatments are also discussed, which will provide a basis to develop novel anti-aging therapeutics for improving the healthspan and preventing aging-related diseases.

Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and d-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging

Abstract: Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in d-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), d-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.

Evidence from two cohorts for the frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems

Abstract: Frailty is a clinical syndrome often present in older adults and characterized by a heightened vulnerability to stressors. The biological antecedents and etiology of frailty are unclear despite decades of research: frailty is associated with dysregulation in a wide range of physiological systems, but no specific cause has been identified. Here, we test predictions stemming from the hypothesis that there is no specific cause: that frailty is an emergent property arising from the complex systems dynamics of the broad loss of organismal homeostasis. Specifically, we use dysregulation of six physiological systems using the Mahalanobis distance approach in two cohorts of older adults to test the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We find clear support for the breadth of associations between frailty and physiological dysregulation: positive associations of all systems with frailty in at least some analyses. We find partial support for diffuseness: the number of systems or total amount of dysregulation is more important than the identity of the systems dysregulated, but results only partially replicate across cohorts. We find partial support for nonlinearity: trends are exponential but not always significantly so, and power is limited for groups with very high levels of dysregulation. Overall, results are consistent with-but not definitive proof of-frailty as an emergent property of complex systems dynamics. Substantial work remains to understand how frailty relates to underlying physiological dynamics across systems.

Anti-SASP and anti-inflammatory activity of resveratrol, curcumin and β-caryophyllene association on human endothelial and monocytic cells

Abstract: A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal β-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1β and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1β, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells.

Low-dose ionizing radiation as a hormetin: experimental observations and therapeutic perspective for age-related disorders

Abstract: Hormesis is any kind of biphasic dose-response when low doses of some agents are beneficial while higher doses are detrimental. Radiation hormesis is the most thoroughly investigated among all hormesis-like phenomena, in particular in biogerontology. In this review, we aimed to summarize research evidence supporting hormesis through exposure to low-dose ionizing radiation (LDIR). Radiation-induced longevity hormesis has been repeatedly reported in invertebrate models such as C. elegans, Drosophila and flour beetles and in vertebrate models including guinea pigs, mice and rabbits. On the contrary, suppressing natural background radiation was repeatedly found to cause detrimental effects in protozoa, bacteria and flies. We also discussed here the possibility of clinical use of LDIR, predominantly for age-related disorders, e.g., Alzheimer's disease, for which no remedies are available. There is accumulating evidence that LDIR, such as those commonly used in X-ray imaging including computer tomography, might act as a hormetin. Of course, caution should be exercised when introducing new medical practices, and LDIR therapy is no exception. However, due to the low average residual life expectancy in old patients, the short-term benefits of such interventions (e.g., potential therapeutic effect against dementia) may outweigh their hypothetical delayed risks (e.g., cancer). We argue here that assessment and clinical trials of LDIR treatments should be given priority bearing in mind the enormous economic, social and ethical implications of potentially-treatable, age-related disorders.

The greatest risk factor for the leading cause of death is ignored.

Abstract: All major United States institutional advocates for research on the biology of aging and for the leading causes of death assert that aging is the greatest risk factor for these deaths. Nevertheless, all fail to support research on the etiology of aging despite having mechanisms to do so. Aging is a problem in physics and not biology. It is a multibillion dollar miss-understanding to believe that the resolution of any or all age associated diseases will reveal information on the underlying aging process. The goal in research on the etiology of aging is to use the new revolutionary methods to study single molecules and their constituent atoms to uncover the qualitative and quantitative status of molecules in old cells that differ from that in young cells. These differences are the conditions that can explain why a common cause may exist for the risk factor for all age-associated diseases. The tyranny of the phrase "research on aging" could apply to almost any human institution. In the absence of a strict definition when used it has become a costly error in gerontology communication. Research on the biology of aging has become its greatest victim. Because aging is a universal manifestation of the fate of all matter, it is the provenance of the National Science Foundation because its stated purpose excludes research in the medical sciences.

Lipids: biomarkers of healthy aging

Abstract: Life expectancy, and longevity have been increasing in recent years However, this is, in most cases, accompanied by age-related diseases Thus, it became essential to better understand the mechanisms inherent to aging, and to establish biomarkers that characterize this physiological process Among all biomolecules, lipids appear to be a good target for the study of these biomarkers In fact, some lipids have already been associated with age-related diseases With the development of analytical techniques such as Mass Spectrometry, and Nuclear Magnetic Resonance, Lipidomics has been increasingly used to study pathological, and physiological states of an organism Thus, the study of serum, and plasma lipidome in centenarians, and elderly individuals without age-related diseases can be a useful tool for the identification of aging biomarkers, and to understand physiological aging, and longevity This review focus on the importance of lipids as biomarkers of aging, and summarize the changes in the lipidome that have been associated with aging, and longevity

A collective analysis of lifespan-extending compounds in diverse model organisms, and of species whose lifespan can be extended the most by the application of compounds.

Abstract: Research on aging and lifespan-extending compounds has been carried out using diverse model organisms, including yeast, worms, flies and mice. Many studies reported the identification of novel lifespan-extending compounds in different species, some of which may have the potential to translate to the clinic. However, studies collectively and comparatively analyzing all the data available in these studies are highly limited. Here, by using data from the DrugAge database, we first identified top compounds in terms of their effects on percent change in average lifespan of diverse organisms, collectively (n = 1728). We found that, when data from all organisms studied were combined for each compound, aspirin resulted in the highest percent increase in average lifespan (52.01%), followed by minocycline (27.30%), N-acetyl cysteine (17.93%), nordihydroguaiaretic acid (17.65%) and rapamycin (15.66%), in average. We showed that minocycline led to the highest percent increase in average lifespan among other compounds, in both Drosophila melanogaster (28.09%) and Caenorhabditis elegans (26.67%), followed by curcumin (11.29%) and gluconic acid (5.51%) for D. melanogaster and by metformin (26.56%), resveratrol (15.82%) and quercetin (9.58%) for C. elegans. Moreover, we found that top 5 species whose lifespan can be extended the most by compounds with lifespan-extending properties are Philodina acuticornis, Acheta domesticus, Aeolosoma viride, Mytilina brevispina and Saccharomyces cerevisiae (211.80%, 76%, 70.26%, 55.18% and 45.71% in average, respectively). This study provides novel insights on lifespan extension in model organisms, and highlights the importance of databases with high quality content curated by researchers from multiple resources, in aging research.

Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.

Abstract: An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-a-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.

Daily ingestion of Akkermansia mucciniphila for one month promotes healthy aging and increases lifespan in old female mice

Abstract: The ingestion of certain probiotics has been suggested as a promising nutritional strategy to improve aging. The objective of this work was to evaluate the effects of the daily intake, for a month, of a new probiotic Akkermansia muciniphila (AKK) (2 × 108 cfu/100µL PBS) on behavior, as well as function and redox state of immune cells of old female ICR-CD1 mice (OA group). For this, several behavioral tests were performed, and function and oxidative-inflammatory stress parameters of peritoneal leukocytes were analyzed in OA group, in a group of the same age that did not take AKK (old control, OC group) and in another adult control (AC) group. The results showed, in OA group, a significant improvement of several behavioral responses (coordination, balance, neuromuscular vigor, exploratory ability and anxiety like-behaviors), as well as in immune functions (chemotaxis, phagocytosis, NK activity and lymphoproliferation) and in oxidative stress parameters (glutathione peroxidase and reductase activities, oxidized glutathione and lipid oxidation concentrations) of the peritoneal leukocytes in comparison to those observed in OC group. In addition, peritoneal immune cells from the OA group released lower basal concentrations of pro-inflammatory cytokines (IL-2, IL-6 and TNF-α) compared to those from the OC group. The values of parameters in OA were similar to those in AC group. These improvements in the old mice receiving the probiotic were reflected in an increase in their lifespan. In conclusion, our data indicate that AKK supplementation for a short period could be a good nutritional strategy to promote healthy longevity.

Astaxanthin protects oxidative stress mediated DNA damage and enhances longevity in Saccharomyces cerevisiae.

Abstract: Reactive oxygen species (ROS) have long been found to play an important role in oxidative mediated DNA damage. Fortunately, cells possess an antioxidant system that can neutralize ROS. However, oxidative stress occurs when antioxidants are overwhelmed by ROS or impaired antioxidant pathways. This study was carried out to find the protective effect of astaxanthin on the yeast DNA repair-deficient mutant cells under hydrogen peroxide stress. The results showed that astaxanthin enhances the percent cell growth of rad1∆, rad51∆, apn1∆, apn2∆ and ogg1∆ cells. Further, the spot test and colony-forming unit count results confirmed that astaxanthin protects DNA repair mutant cells from oxidative stress. The DNA binding property of astaxanthin studied by in silico and in vitro methods indicated that astaxanthin binds to the DNA in the major and minor groove, and that might protect DNA against oxidative stress induced by Fenton's reagent. The intracellular ROS, 8-OHdG level and the DNA fragmentation as measured by comet tail was reduced by astaxanthin under oxidative stress. Similarly, reduced nuclear fragmentation and chromatin condensation results suggest that astaxanthin might reduce apoptosis. Finally, we show that astaxanthin decreases the accumulation of mutation rate and enhances the longevity of DNA repair-deficient mutants' cells during a chronological lifespan.

Metolazone upregulates mitochondrial chaperones and extends lifespan in Caenorhabditis elegans.

Abstract: Accumulating studies have argued that the mitochondrial unfolded protein response (UPRmt) is a mitochondrial stress response that promotes longevity in model organisms. In the present study, we screened an off-patent drug library to identify compounds that activate UPRmt using a mitochondrial chaperone hsp-6::GFP reporter system in Caenorhabditis elegans. Metolazone, a diuretic primarily used to treat congestive heart failure and high blood pressure, was identified as a prominent hit as it upregulated hsp-6::GFP and not the endoplasmic reticulum chaperone hsp-4::GFP. Furthermore, metolazone specifically induced the expression of mitochondrial chaperones in the HeLa cell line. Metolazone also extended the lifespan of worms in a atfs-1 and ubl-5-dependent manner. Notably, metolazone failed to increase lifespan in worms with knocked-down nkcc-1. These results suggested that metolazone activates the UPRmt across species and prolongs the lifespan of C. elegans.

Inhibition of mTOR decreases insoluble proteins burden by reducing translation in C. elegans

Abstract: Aging animals accumulate insoluble proteins as a consequence of a decline of proteostatic maintenance with age. In Caenorhabditis elegans, for instance, levels of detergent-insoluble proteins increase with age. In longer-lived strains of C. elegans, this accumulation occurs more slowly, implying a link to lifespan determination. We further explored this link and found that detergent-insoluble proteins accumulate more rapidly at higher temperatures, a condition where lifespan is short. We employed a C. elegans strain carrying a GFP transcriptional reporter under the control of a heat shock (hsp-16.2) promoter to investigate the dynamics of proteostatic failure in individual nematodes. We found that early, sporadic activation of hsp-16.2 was predictive of shorter remaining lifespan in individual nematodes. Exposure to rapamycin, resulting in reduced mTOR signaling, delayed spurious expression, extended lifespan, and delayed accumulation of insoluble proteins, suggesting that targets downstream of the mTOR pathway regulate the accumulation of insoluble proteins. We specifically explored ribosomal S6 kinase (rsks-1) as one such candidate and found that RNAi against rsks-1 also resulted in less age-dependent accumulation of insoluble proteins and extended lifespan. Our results demonstrate that inhibition of protein translation via reduced mTOR signaling resulted in slower accumulation of insoluble proteins, delayed proteostatic crisis, and extended lifespan in C. elegans.

Targeting Wnt signaling pathway by polyphenols: implication for aging and age-related diseases

Abstract: Age is an important risk factor for different diseases. The same mechanisms that promote aging are involved in the development and progression of age-associated diseases. Polyphenols are organic compounds found in fruits and vegetables. Due to their beneficial properties (e.g. antioxidant and anti-inflammatory), polyphenols have been extensively used for treating chronic diseases. To exert their functions, polyphenols target various molecular mechanisms and signaling pathways, such as mTOR, NF-κB, and Wnt/β-catenin. Wnt signaling is a critical pathway for developmental processes. Besides, dysregulation of this signaling pathway has been observed in various diseases. Several investigations have been conducted on Wnt inhibitors at pre-clinical stages, showing promising results. Herein, we review the studies dealing with the role of polyphenols in targeting the Wnt signaling pathways in aging processes and age-associated diseases, including cancer, diabetes, Alzheimer's disease, osteoporosis, and Parkinson's disease.

Health and longevity studies in C. elegans : the “healthy worm database” reveals strengths, weaknesses and gaps of test compound-based studies

Abstract: Several biogerontology databases exist that focus on genetic or gene expression data linked to health as well as survival, subsequent to compound treatments or genetic manipulations in animal models. However, none of these has yet collected experimental results of compound-related health changes. Since quality of life is often regarded as more valuable than length of life, we aim to fill this gap with the "Healthy Worm Database" ( http://healthy-worm-database.eu ). Literature describing health-related compound studies in the aging model Caenorhabditis elegans was screened, and data for 440 compounds collected. The database considers 189 publications describing 89 different phenotypes measured in 2995 different conditions. Besides enabling a targeted search for promising compounds for further investigations, this database also offers insights into the research field of studies on healthy aging based on a frequently used model organism. Some weaknesses of C. elegans-based aging studies, like underrepresented phenotypes, especially concerning cognitive functions, as well as the convenience-based use of young worms as the starting point for compound treatment or phenotype measurement are discussed. In conclusion, the database provides an anchor for the search for compounds affecting health, with a link to public databases, and it further highlights some potential shortcomings in current aging research.

Analysis of longevity in Chordata identifies species with exceptional longevity among taxa and points to the evolution of longer lifespans

Abstract: Animals have a considerable variation in their longevity This fundamental life-history trait is shaped by both intrinsic and extrinsic mortality pressures, influenced by multiple parameters including ecological variables and mode-of-life traits Here, we examined the distribution of maximum age at multiple taxonomic ranks (class, order and family) in Chordata, and identified species with exceptional longevity within various taxa We used a curated dataset of maximum longevity of animals from AnAge database, containing a total of 2542 chordates following our filtering criteria We determined shapes of maximum age distributions at class, order and family taxonomic ranks, and calculated skewness values for each distribution, in R programming environment We identified species with exceptional longevity compared to other species belonging to the same taxa, based on our definition of outliers We collected data on ecological variables and mode-of-life traits which might possibly contribute, at least in part, to the exceptional lifespans of certain chordates We found that 23, 12 and 4 species have exceptional longevity when we grouped chordates by their class, order and family, respectively Almost all distributions of maximum age among taxa were positively skewed (towards increased longevity), possibly showing the emergence of longer lifespans in contrast to shorter lifespans, through the course of evolution However, potential biases in the collection of data should be taken into account Most of the identified species in the current study have not been previously studied in the context of animal longevity Our analyses point that certain chordates may have evolved to have longer lifespans compared to other species belonging to the same taxa, and that among taxa, outliers in terms of maximum age have always longer lifespans, not shorter Future research is required to understand how and why increased longevity have arose in certain species

Exercise renovates H2S and Nrf2-related antioxidant pathways to suppress apoptosis in the natural ageing process of male rat cortex.

Abstract: Ageing is a complex biological process that increases the probability of disease and death, which affects the organs of all species. The accumulation of oxidative damage in the brain contributes to a progressive loss of cognitive functions or even declined the energy metabolism. In this study, we tested the effects of exercise training on the apoptosis, survival, and antioxidant signaling pathways in the cerebral cortex of three age groups of male rats; 3, 12, and 18 months. We observed that H2S and the expression of Nrf2-related antioxidant pathways declined with age and increased after exercise training. IGF1R survival pathway was less increased in middle-aged rats; however, significantly increased after exercise training. The expression of mitochondrial-dependent apoptotic pathway components, such as Bak, cytochrome C, and caspase 3 in the ageing control group, were much higher than those of the exercise training groups. This study demonstrated that exercise training could reduce the apoptosis and oxidative stress that accrues throughout ageing, which causes brain damage.

Background radiation impacts human longevity and cancer mortality: reconsidering the linear no-threshold paradigm.

Abstract: The current linear no-threshold paradigm assumes that any exposure to ionizing radiation carries some risk, thus every effort should be made to maintain the exposures as low as possible. We examined whether background radiation impacts human longevity and cancer mortality. Our data covered the entire US population of the 3139 US counties, encompassing over 320 million people. This is the first large-scale study which takes into account the two major sources of background radiation (terrestrial radiation and cosmic radiation), covering the entire US population. Here, we show that life expectancy, the most integrative index of population health, was approximately 2.5 years longer in people living in areas with a relatively high vs. low background radiation. (≥ 180 mrem/year and ≤ 100 mrem/year, respectively; p < 0.005; 95% confidence interval [CI]). This radiation-induced lifespan extension could to a great extent be associated with the decrease in cancer mortality rate observed for several common cancers (lung, pancreas and colon cancers for both genders, and brain and bladder cancers for males only; p < 0.05; 95% CI). Exposure to a high background radiation displays clear beneficial health effects in humans. These hormetic effects provide clear indications for re-considering the linear no-threshold paradigm, at least within the natural range of low-dose radiation.

Geroprotective potential of genetic and pharmacological interventions to endogenous hydrogen sulfide synthesis in Drosophila melanogaster.

Abstract: Endogenous hydrogen sulfide (H2S) is a gasotransmitter with a wide range of physiological functions. Aging is accompanied by disruption of H2S homeostasis, therefore, interventions to the processes of H2S metabolism to maintain its balance may have geroprotective potential. Here we demonstrated the additive geroprotective effect of combined genetic and pharmacological interventions to the hydrogen sulfide biosynthesis system by overexpression of cystathionine-β-synthase and cystathionine-γ-lyase genes and treatment with precursors of H2S synthesis cysteine (Cys) and N-acetyl-L-cysteine (NAC). The obtained results suggest that additive effects of genetic and pharmacological interventions to H2S metabolism may be associated with the complex interaction between beneficial action of H2S production and prevention of adverse effects of excess H2S production by Cys and NAC treatment.

Sarcopenia versus cancer cachexia: the muscle wasting continuum in healthy and diseased aging

Abstract: Muscle wasting is one of the major health problems in older adults and is traditionally associated to sarcopenia. Nonetheless, muscle loss may also occur in older adults in the presence of cancer, and in this case, it is associated to cancer cachexia. The clinical management of these conditions is a challenge due to, at least in part, the difficulties in their differential diagnosis. Thus, efforts have been made to better comprehend the pathogenesis of sarcopenia and cancer cachexia, envisioning the improvement of their clinical discrimination and treatment. To add insights on this topic, this review discusses the current knowledge on key molecular players underlying sarcopenia and cancer cachexia in a comparative perspective. Data retrieved from this analysis highlight that while sarcopenia is characterized by the atrophy of fast-twitch muscle fibers, in cancer cachexia an increase in the proportion of fast-twitch fibers appears to happen. The molecular drivers for these specificmuscle remodeling patterns are still unknown; however, among the predominant contributors to sarcopenia is the age-induced neuromuscular denervation, and in cancer cachexia, the muscle disuse experienced by cancer patients seems to play an important role. Moreover, inflammation appears to be more severe in cancer cachexia. Impairment of nutrition-related mediators may also contribute to sarcopenia and cancer cachexia, being distinctly modulated in each condition.

Tracing skin aging process: a mini- review of in vitro approaches

Abstract: Skin is a rather complex, yet useful organ of our body. Besides, skin aging is a complicated process that gains a growing interest as mediates many molecular processes in our body. Thus, an efficient skin model is important to understand skin aging function as well as to develop an effective innovative product for skin aging treatment. In this mini review, we present in vitro methods for assessments of skin aging in an attempt to pinpoint basic molecular mechanisms behind this process achieving both a better understanding of aging function and an effective evaluation of potential products or ingredients that counteract aging. Specifically, this study presents in vitro assays such as 2D or 3D skin models, to evaluate skin aging-related processes such as skin moisturization, photoaging, wound healing, menopause, and skin microbiome as novel efforts in the designing of efficacy assessments in the development of skincare products.

ATP-dependent chromatin remodelers in ageing and age-related disorders.

Abstract: Ageing is characterized by the perturbation in cellular homeostasis associated with genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intracellular communication. Changes in the epigenome represent one of the crucial mechanisms during ageing and in age-related disorders. The ATP-dependent chromatin remodelers are an evolutionarily conserved family of nucleosome remodelling factors and generally regulate DNA repair, replication, recombination, transcription and cell cycle. Here, we review the chromatin based epigenetic changes that occur in ageing and age-related disorders with a specific reference to chromatin remodelers. We also discuss the link between dietary restriction and chromatin remodelers in regulating age-related processes with a view for consideration in future intervention studies.

Production and scavenging of reactive oxygen species both affect reproductive success in male and female Drosophila melanogaster

Abstract: Sperm aging is accelerated by the buildup of reactive oxygen species (ROS), which cause oxidative damage to various cellular components. Aging can be slowed by limiting the production of mitochondrial ROS and by increasing the production of antioxidants, both of which can be generated in the sperm cell itself or in the surrounding somatic tissues of the male and female reproductive tracts. However, few studies have compared the separate contributions of ROS production and ROS scavenging to sperm aging, or to cellular aging in general. We measured reproductive fitness in two lines of Drosophila melanogaster genetically engineered to (1) produce fewer ROS via expression of alternative oxidase (AOX), an alternative respiratory pathway; or (2) scavenge fewer ROS due to a loss-of-function mutation in the antioxidant gene dj-1β. Wild-type females mated to AOX males had increased fecundity and longer fertility durations, consistent with slower aging in AOX sperm. Contrary to expectations, fitness was not reduced in wild-type females mated to dj-1β males. Fecundity and fertility duration were increased in AOX and decreased in dj-1β females, indicating that female ROS levels may affect aging rates in stored sperm and/or eggs. Finally, we found evidence that accelerated aging in dj-1β sperm may have selected for more frequent mating. Our results help to clarify the relative roles of ROS production and ROS scavenging in the male and female reproductive systems.

Age-dependent effect of continuous 'artificial light at night' on circadian rhythm in male rats: neuroprotective role of melatonin.

Abstract: Circadian disruption due to artificial light at night (ALAN) is an alarming threat to modern society. In the present study we evaluated the protective effect of melatonin on age dependent redox insults and neurochemical deficits induced by ALAN in the brain of chronodisrupted rat model. Young (3 months) and old (22 months) male Wistar rats were exposed to ALAN along with melatonin supplementation (10 mg Kg−1, oral) for 10 days. Results demonstrated significant increment in the pro-oxidant biomarkers: reactive oxygen species, lipid hydroperoxidation, protein carbonyl, nitric oxide while suppression in the total thiol, ferric reducing antioxidant potential level, superoxide dismutase and catalase activities in the brain of ALAN exposed groups with higher amplitude in aged rats. Further these oxidative modifications were protected by subsequent administration of melatonin. Mitochondrial complexes (C-I to C-IV) activity was significantly altered in young and old ALAN exposed groups with melatonin showing protective effect. Histopathological analysis show dense cytosolic staining and neuronal degeneration in cerebral cortex and different hippocampus regions with greater extent in old ALAN rats effectively moderated by melatonin supplementation. RT-PCR data analysis revealed melatonin effectively downregulated neuroinflammatory (IL-6, TNF α) and neurodegenerative marker (Ngb) while upregulating the aging (Sirt 1) gene expression in both young and old melatonin supplemented ALAN exposed groups. Our results may help in understanding the degree of ALAN induced photo-oxidative damage in neuronal redox homeostasis during aging. We also show that melatonin supplementation might provide a basis for amelioration of oxidative disturbances to improve circadian entrainment in aged populations.

The seesaw of diet restriction and lifespan: lessons from Drosophila studies.

Abstract: Diet restriction (DR) studies undergo the implementation of reduced single or multiple component/s of the fly food without causing malnutrition. The question of how and why DR modifies the fate of lifespan in fruit flies Drosophila melanogaster has prompted us to emphasize by attending the control food composition first. Certain concentrations of DR food do not always confer an extended lifespan, rather it enables the flies to achieve their normal lifespan, which was probably reduced by the control food per se (having toxic effect caused due to the excess levels of dietary components). However, the current paradigm of DR studies has elicited its benefits and losses via trade-offs in the organismal traits and have highlighted the need for a common diet, but have not claimed the tested diets as balanced. So, the DR effect on lifespan and other fitness traits cannot be justified only based on varying control food across labs and hence, the approach of DR studies has to be revisited and a balanced diet has to be formulated. The current article discusses the need for a balanced diet, the traits to be considered before designing a diet, and certain problems in the existing synthetic medium. Therefore, based on the control food composition, the validity of lifespan extension conferred by these nutrient restricted diets need to be accounted for.

Application of lipidomics strategy to explore aging-related biomarkers and potential anti-aging mechanisms of ginseng.

Abstract: Aging often leads to an increase risk of age-related diseases, and the development of anti-aging drugs have become the trend and focus of the current scientific research. In this experiment, serum samples from healthy people of different ages were analyzed based on clinical lipidomics, and a total of 10 potential biomarkers in middle-aged and youth group, 20 biomarkers in the youth and the elderly group were obtained. Furthermore, dhSph and dhCer involved above may affect the aging process through sphingolipid metabolic pathway. As the first and rate-limiting step of catalyzing de novo sphingolipid pathway, SPT may play a key role in human anti-aging, which is revealed by lipidomics liposome tracer analysis. The potential active components in ginseng on SPT was further verified by molecular docking virtual screening and atomic force microscope. Four ingredients of ginseng may reduce the levels of metabolites dhSph and dhCer by inhibiting the activity of SPT, and play an anti-aging effect by affecting the sphingolipid metabolism pathway.A clinical trials registration number: ChiCTR1900026836.

Sex-related differences in behavioural markers in adult mice for the prediction of lifespan

Abstract: Finding biomarkers to assess the rate of ageing and consequently, to forecast individual lifespan is a challenge in ageing research. We recently published a mathematical model for lifespan prediction in adult female mice using behavioural parameters such as internal locomotion and time spent in open arms in the hole board (HB) and elevated plus maze (EPM) tests, respectively. Nevertheless, it is still not known if these behavioural variables could be useful in forecasting lifespan in male mice. Therefore, two groups of ICR-CD1 mice, male and female were subjected to the EPM, HB and T-maze tests at the adult age. Mice were monitored until they died and individual lifespans were registered. In general, adult male mice showed more anxiety-like behaviours than females. The mathematical model previously developed in females was validated with the female cohort, but found to be suboptimal for lifespan prediction in males. Thus, a new model for male lifespan prediction was constructed including the behavioural variables that were predictive of lifespan in males: time in the central platform of the EPM, inner locomotion, number of groomings and number and duration of head-dippings in the HB. These results confirm that the higher the anxiety-like behaviour at the adult age, the shorter the lifespan.

Responsible biology, aging populations and the 50th anniversary of the "War on Cancer"

Abstract: The 50th Anniversary of the National Cancer Act of 1971 is the opportune time to critically reflect on the determinates of what the philosopher of science Philip Kitcher calls "responsible biology". Responsible biology entails that scientists have an obligation to reflect on the ends, and not just the means, of scientific research and to conceive of themselves as artisans working for the public good. Taking stock of the successes and limits of the half a century "war on cancer" reveals the importance of attending to the most significant risk factor for cancer and other chronic diseases- aging itself. The case is made for considering the biology of aging, and the aspiration to slow the rate of biological aging, as critical components of responsible biology in an aging world. As growing numbers of humans survive into late life, the primacy the goal of disease elimination occupies within biomedical research must be revised, and greater effort should be directed towards the goal of increasing the human healthspan and delaying and compressing disease, frailty and disability in late life.

An essay on the nominal vs. real definitions of aging.

Abstract: In the current literature, the definitions of aging range from relying on certain sets of distinctive features at the molecular, organismal, populational and/or even evolutional levels/scales to declaring it a treatable disease and, moreover, to treating aging as a mental construct rather than a natural phenomenon. One reason of such a mess may be that it is common in the natural sciences to disregard philosophy of science where several categories of definitions are recognized, among which the nominal are less, and the so-called real ones are more appropriate in scientific contexts. E.g., water is, by its nominal definition, a liquid having certain observable features and, by its real definition, a specific combination (or a product of interaction) of hydrogen and oxygen atoms. Noteworthy, the real definition is senseless for people ignorant of atoms. Likewise, the nominal definition of aging as a set of observable features should be supplemented, if not replaced, with its real definition. The latter is suggested here to imply that aging is the product of chemical interactions between the rapidly turning-over free metabolites and the slowly turning-over metabolites incorporated in macromolecules involved in metabolic control. The phenomenon defined in this way emerged concomitantly with metabolic pathways controlled by enzymes coded for by information-storing macromolecules and is inevitable wherever such conditions coincide. Aging research, thus, is concerned with the elucidation of the pathways and mechanisms that link aging defined as above to its hallmarks and manifestations, including those comprised by its nominal definitions. Esoteric as it may seem, defining aging is important for deciding whether aging is what should be declared as the target of interventions aimed at increasing human life and health spans.

Middle aged turn point in parameters of oxidative stress and glucose catabolism in mouse cerebellum during lifespan: minor effects of every-other-day fasting.

Abstract: The cerebellum is considered to develop aging markers more slowly than other parts of the brain. Intensification of free radical processes and compromised bioenergetics, critical hallmarks of normal brain aging, may be slowed down by caloric restriction. This study aimed to evaluate the intensity of oxidative stress and the enzymatic potential to utilize glucose via glycolysis or the pentose phosphate pathway (PPP) in the cerebellum of mice under ad libitum versus every-other-day fasting (EODF) feeding regimens. Levels of lipid peroxides, activities of antioxidant and key glycolytic and PPP enzymes were measured in young (6-month), middle-aged (12-month) and old (18-month) C57BL/6J mice. The cerebellum showed the most dramatic increase in lipid peroxide levels, antioxidant capacity and PPP key enzyme activities and the sharpest decline in the activities of key glycolytic enzymes under transition from young to middle age but these changes slowed when transiting from middle to old age. A decrease in the activity of the key glycolytic enzyme phosphofructokinase was accompanied by a concomitant increase in the activities of hexokinase and glucose-6-phosphate dehydrogenase (G6PDH), which may suggest that during normal cerebellar aging glucose metabolism shifts from glycolysis to the pentose phosphate pathway. The data indicate that intensification of free radical processes in the cerebellum occurred by middle age and that activation of the PPP together with increased antioxidant capacity can help to resist these changes into old age. However, the EODF regime did not significantly modulate or alleviate any of the metabolic processes studied in this analysis of the aging cerebellum.