Role of epigenetics in the regulation of skin aging and geroprotective intervention: A new sight.

Multiple epigenetic factors play a regulatory role in maintaining the homeostasis of cutaneous components and are implicated in the aging process of the skin. They have been associated with the activation of the senescence program, which is the primary contributor to age-related decline in the skin. Senescent species drive a series of interconnected processes that impact the immediate surroundings, leading to structural changes, diminished functionality, and heightened vulnerability to infections. Geroprotective medicines that may restore the epigenetic balance represent valid therapeutic alliances against skin aging. Most of them are well-known Western medications such as metformin, nicotinamide adenine dinucleotide (NAD+), rapamycin, and histone deacetylase inhibitors, while others belong to Traditional Chinese Medicine (TCM) remedies for which the scientific literature provides limited information. With the help of the Geroprotectors.org database and a comprehensive analysis of the referenced literature, we have compiled data on compounds and formulae that have shown potential in preventing skin aging and have been identified as epigenetic modulators.

Gut microb-aging and its relevance to frailty aging.

This review explores 'microb-aging' in the gut and its potential link to frailty aging. We explore this connection through alterations in microbiota's taxonomy and metabolism, as well as with concepts of ecological resilience, pathobionts emergence, and biogeography. We examine microb-aging in interconnected body organs, emphasizing the bidirectional relationship with 'inflammaging'. Finally, we discuss how targeting microb-aging could improve screening, diagnostic, and therapeutic approaches in geriatrics.

Polyphenols as Potential Geroprotectors.

Significance: Currently, a large amount of evidence of beneficial effects of diets enriched with polyphenols on various aspects of health has been accumulated. These phytochemicals have a geroprotective potential slowing down the pathological processes associated with aging and ensuring longevity. In this study, a comprehensive analysis was conducted to determine the adherence of individual polyphenols to geroprotector criteria. Data from experimental models, clinical trials, and epidemiological studies were analyzed. Recent Advances: Sixty-two polyphenols have been described to increase the life span and improve biomarkers of aging in animal models. They act via evolutionarily conserved molecular mechanisms, including hormesis and maintenance of redox homeostasis, epigenetic regulation, response to cellular damage, metabolic control, and anti-inflammatory and senolytic activity. Epidemiological and clinical studies suggest that certain polyphenols have a potential for prevention and treatment of various diseases, including cancer, metabolic disorders, and cardiovascular conditions in humans. Critical Issues: Among the reviewed phytochemicals, chlorogenic acid, quercetin, epicatechin, genistein, resveratrol, and curcumin were identified as compounds with the highest geroprotective potential. However, there is a lack of unambiguous information on the effectiveness and safety of polyphenols for increasing health span, preventing and treating aging-associated diseases in humans. Future Directions: Further research is needed to fully understand the effects of polyphenols considering their long-term consumption, metabolic modification and bioavailability, complex interactions between different groups of polyphenols and with other phytochemicals, as well as their effects on individuals with different health status. Antioxid. Redox Signal. 40, 564-593.

The effect of glycine administration on the characteristics of physiological systems in human adults: A systematic review.

Functional decline of physiological systems during ageing leads to age-related diseases. Dietary glycine increases healthy lifespan in model organisms and might decrease inflammation in humans, suggesting its geroprotective potential. This review summarises the evidence of glycine administration on the characteristics of eleven physiological systems in adult humans. Databases were searched using key search terms: 'glycine', 'adult', 'supplementation'/ 'administration'/ 'ingestion'/ 'treatment'. Glycine was administered to healthy and diseased populations (18 and 34 studies) for up to 14 days and 4 months, respectively. The nervous system demonstrated the most positive effects, including improved psychiatric symptoms from longer-term glycine administration in psychiatric populations. While longer-term glycine administration improved sleep in healthy populations, these studies had small sample sizes with a high risk of bias. Larger and long-term studies with more robust study designs in healthy populations to examine the effects of glycine administration on preventing, delaying or reversing the ageing process are warranted.

Optimization of parameters for obtaining callus, suspension, and root cultures of meadowsweet (filipendula ulmaria) to isolate the largest number of biologically active substances with geroprotective properties

Abstract The study of biologically active substances-secondary metabolites of plants that exhibit geroprotective properties is an actual and popular direction in medicine to prevent early aging. This work aims to select the cultivation parameters for obtaining in vitro cell cultures of meadowsweet containing the largest amount of biologically active substances (BAS) for their further extraction as candidate substances for geroprotectors. To specify the effectiveness of the selected cell culture cultivation parameters, biomass growth for callus and root cultures, growth index, specific growth rate, and viability for suspension cultures was carried out. The study results made it possible to select the nutrient media for the cultivation of cell cultures of meadowsweet. It has been found that the greater the antioxidant activity of the extracts, the greater the antimicrobial properties it exhibits. In this study, cell cultures in vitro and alcohol extracts from the plant Filipendula ulmaria were considered as raw materials rich in candidate substances for geroprotectors. According to the data obtained, the plant is rich in hydroxybenzoic and salicylic acids, spireoside, avicularin, and hyperoside.

Resumo O estudo de substâncias biologicamente ativas metabólitos secundários de plantas que apresentam propriedades geroprotetoras é uma tendência atual e popular no campo da medicina para a prevenção do envelhecimento precoce. O objetivo deste trabalho foi selecionar os parâmetros de cultivo para obtenção de culturas celulares in vitro de Ulmária contendo a maior quantidade de substâncias biologicamente ativas (SBA), para sua posterior extração como substâncias candidatas a serem geroprotetoras. Para especificar a eficácia dos parâmetros selecionados de cultivo em cultura de células, foi realizada a análise de crescimento de biomassa para culturas de calos e raízes, índice de crescimento, taxa de crescimento específica e viabilidade para culturas em suspensão. Os resultados do estudo possibilitaram a seleção do meio nutriente para o cultivo de células de Ulmária. Verificou-se que, quanto maior a atividade antioxidante dos extratos, maiores eram as propriedades antimicrobianas exibidas. Neste estudo, culturas celulares in vitro e extratos alcoólicos da planta Filipendula ulmaria foram considerados matérias-primas ricas em substâncias candidatas a serem geroprotetoras. De acordo com os dados obtidos, a planta é rica em ácidos hidroxibenzoico e salicílico, espirosídeo, avicularina e hiperosídeo.

Optimization of parameters for obtaining callus, suspension, and root cultures of meadowsweet (filipendula ulmaria) to isolate the largest number of biologically active substances with geroprotective properties / Otimização de parâmetros para obtenção de culturas de calos, suspensão e raiz de Ulmária (Filipendula ulmaria) para isolar o maior número de substâncias biologicamente ativas com propriedades geroprotetoras

The study of biologically active substances-secondary metabolites of plants that exhibit geroprotective properties is an actual and popular direction in medicine to prevent early aging. This work aims to select the cultivation parameters for obtaining in vitro cell cultures of meadowsweet containing the largest amount of biologically active substances (BAS) for their further extraction as candidate substances for geroprotectors. To specify the effectiveness of the selected cell culture cultivation parameters, biomass growth for callus and root cultures, growth index, specific growth rate, and viability for suspension cultures was carried out. The study results made it possible to select the nutrient media for the cultivation of cell cultures of meadowsweet. It has been found that the greater the antioxidant activity of the extracts, the greater the antimicrobial properties it exhibits. In this study, cell cultures in vitro and alcohol extracts from the plant Filipendula ulmaria were considered as raw materials rich in candidate substances for geroprotectors. According to the data obtained, the plant is rich in hydroxybenzoic and salicylic acids, spireoside, avicularin, and hyperoside.

O estudo de substâncias biologicamente ativas - metabólitos secundários de plantas que apresentam propriedades geroprotetoras - é uma tendência atual e popular no campo da medicina para a prevenção do envelhecimento precoce. O objetivo deste trabalho foi selecionar os parâmetros de cultivo para obtenção de culturas celulares in vitro de Ulmária contendo a maior quantidade de substâncias biologicamente ativas (SBA), para sua posterior extração como substâncias candidatas a serem geroprotetoras. Para especificar a eficácia dos parâmetros selecionados de cultivo em cultura de células, foi realizada a análise de crescimento de biomassa para culturas de calos e raízes, índice de crescimento, taxa de crescimento específica e viabilidade para culturas em suspensão. Os resultados do estudo possibilitaram a seleção do meio nutriente para o cultivo de células de Ulmária. Verificou-se que, quanto maior a atividade antioxidante dos extratos, maiores eram as propriedades antimicrobianas exibidas. Neste estudo, culturas celulares in vitro e extratos alcoólicos da planta Filipendula ulmaria foram considerados matérias-primas ricas em substâncias candidatas a serem geroprotetoras. De acordo com os dados obtidos, a planta é rica em ácidos hidroxibenzoico e salicílico, espirosídeo, avicularina e hiperosídeo.

[The Antioxidant and Geroprotective Properties of an Extract of Mountain Ash (Sorbus aucuparia L.) Fruits].

Plant polyphenols are characterized by a wide range of biological activities, including antioxidant properties, and have a high geroprotective potential. The purpose of this work was to investigate the effect of the extract of rowan berries (Sorbus aucuparia L.) on the lifespan and stress resistance of Drosophila melanogaster with the identification of possible mechanisms of its biological activity. It has been established that an ethanol extract of S. aucuparia berries, the main components of which are rutin and cyanidin-3-rutinoside, has a pronounced antioxidant activity in vitro. At the same time, treatment with rowan berry extract increased the resistance of D. melanogaster males to starvation, but reduced resistance to hyperthermia. In females, the extract reduced resistance to oxidative stress but increased resistance to hyperthermia. The effects of rowan berry extract on longevity depended both on its concentration and on the sex of fruit flies. In response to treatment with rowan berry extract, D. melanogaster males and females showed slight differences in the background level of expression of cellular stress response genes, including heat shock genes (hsp27, hsp68, and hsp83), oxidative stress resistance genes (hif1, nrf2, and sod1), circadian rhythm genes (clk and per), and the longevity gene sirt1, which may explain the differences in the observed effects.

Potential Geroprotectors - From Bench to Clinic.

Geroprotectors are substances that slow down aging process and can be used for prevention of age-related diseases. Geroprotectors can improve functioning of various organ systems and enhance their homeostatic capabilities. We have developed a system of criteria for geroprotectors and proposed their classification based on the mechanisms of their action on the aging processes. Geroprotectors are required to reduce mortality, improve human aging biomarkers, have minimal side effects, and enhance quality of life. Additionally, there are approaches based on combining geroprotectors targeted to different targets and mechanisms of aging to achieve maximum effectiveness. Currently, numerous preclinical studies are being conducted to identify new molecular targets and develop new approaches to extend healthy aging, although the number of clinical trials is limited. Geroprotectors have the potential to become a new class of preventive medicines as they prevent onset of certain diseases or slow down their progression.

Antioxidant Properties and Geroprotective Potential of Wheat Bran Extracts with Increased Content of Anthocyanins.

In recent years, there has been a focus on breeding wheat with high anthocyanin levels in order to improve food quality and human health. The objective of this study was to examine the antioxidant and geroprotective properties of wheat bran extracts using both in vitro and in vivo research methods. Two wheat lines were used: one with uncolored pericarp (anthocyanin-free) and another with colored pericarp (anthocyanin-containing). These lines differed in a specific region of chromosome 2A containing the Pp3/TaMyc1 gene, which regulates anthocyanin production. High-performance liquid chromatography-mass spectrometry revealed the presence of cyanidin glucoside and cyanidin arabinoside in the anthocyanin-containing wheat bran extract (+AWBE), while no anthocyanins were found in the anthocyanin-free wheat bran extract (-AWBE). The +AWBE showed higher radical scavenging activity (DPPH and ABTS assays) and membrane protective activity (AAPH oxidative hemolysis model) compared to the -AWBE. Both extracts extended the lifespan of female Drosophila, indicating geroprotective properties. This study demonstrates that wheat bran extracts with high anthocyanin levels have antioxidant and geroprotective effects. However, other secondary metabolites in wheat bran can also contribute to its antioxidant and geroprotective potential.

Targeting the epigenetically older individuals for geroprotective trials: the use of DNA methylation clocks.

Chronological age is the most important risk factor for the incidence of age-related diseases. The pace of ageing determines the magnitude of that risk and can be expressed as biological age. Targeting fundamental pathways of human aging with geroprotectors has the potential to lower the biological age and therewith prolong the healthspan, the period of life one spends in good health. Target populations for geroprotective interventions should be chosen based on the ageing mechanisms being addressed and the expected effect of the geroprotector on the primary outcome. Biomarkers of ageing, such as DNA methylation age, can be used to select populations for geroprotective interventions and as a surrogate outcome. Here, the use of DNA methylation clocks for selecting target populations for geroprotective intervention is explored.

Studying the Geroprotective Properties of YAP/TAZ Signaling Inhibitors on Drosophila melanogaster Model.

The transcriptional coactivators Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the main downstream effectors of the evolutionarily conserved Hippo signaling pathway. YAP/TAZ are implicated in the transcriptional regulation of target genes that are involved in a wide range of key biological processes affecting tissue homeostasis and play dual roles in the aging process, depending on the cellular and tissue context. The aim of the present study was to investigate whether pharmacological inhibitors of Yap/Taz increase the lifespan of Drosophila melanogaster. Real-time qRT-PCR was performed to measure the changes in the expression of Yki (Yorkie, the Drosophila homolog of YAP/TAZ) target genes. We have revealed a lifespan-increasing effect of YAP/TAZ inhibitors that was mostly associated with decreased expression levels of the wg and E2f1 genes. However, further analysis is required to understand the link between the YAP/TAZ pathway and aging.

Anti-retroviral treatment with zidovudine alters pyrimidine metabolism, reduces translation, and extends healthy longevity via ATF-4.

The human population is aging, and the need for interventions to slow progression of age-related diseases (geroprotective interventions) is growing. Repurposing compounds already used clinically, usually at modified doses, allows rapid implementation of geroprotective pharmaceuticals. Here we find the anti-retroviral nucleoside reverse transcriptase inhibitor (NRTI) zidovudine robustly extends lifespan and health span in C. elegans, independent of electron transport chain impairment or ROS accumulation. Rather, zidovudine treatment modifies pyrimidine metabolism and transcripts related to proteostasis. Testing regulators of mitochondrial stress and proteostasis shows that lifespan extension is dependent on activating transcription factor 4 (ATF-4). ATF-4 regulates longevity induced by mitochondrial stress, specifically communication between mitochondrial and cytosolic translation. Translation is reduced in zidovudine-treated worms, also dependent on ATF-4. Finally, we show ATF-4-dependent lifespan extension induced by didanosine, another NRTI. Altogether, our work elucidates the geroprotective effects of NRTIs such as zidovudine in vivo, via reduction of translation and ATF-4.

Repurposing digoxin for geroprotection in patients with frailty and multimorbidity.

The geroscience hypothesis proposes biological hallmarks of ageing are modifiable. Increasing evidence supports targeting these hallmarks with therapeutics could prevent and ameliorate age-related conditions - collectively termed "geroprotector drugs". Cellular senescence is a hallmark with considerable potential to be modified with geroprotector drugs. Senotherapeutics are drugs that target cellular senescence for therapeutic benefit. Repurposing commonly used medications with secondary geroprotector properties is a strategy of interest to promote incorporation of geroprotector drugs into clinical practice. One candidate is the cardiac glycoside digoxin. Evidence in mouse models of pulmonary fibrosis, Alzheimer's disease, arthritis and atherosclerosis support digoxin as a senotherapeutic agent. Proposed senolytic mechanisms are upregulation of intrinsic apoptotic pathways and promoting intracellular acidification. Digoxin also appears to have a senomorphic mechanism - altering the T cell pool to ameliorate pro-inflammatory SASP. Despite being widely prescribed to treat atrial fibrillation and heart failure, often in multimorbid older adults, it is not known whether digoxin exerts senotherapeutic effects in humans. Further cellular and animal studies, and ultimately clinical trials with participation of pre-frail older adults, are required to identify whether digoxin has senotherapeutic effect at low dose. This paper reviews the biological mechanisms identified in preliminary cellular and animal studies that support repurposing digoxin as a geroprotector in patients with frailty and multimorbidity.

Biomarkers of geroprotection and cardiovascular health: An overview of omics studies and established clinical biomarkers in the context of diet.

The slowdown, inhibition, or reversal of age-related decline (as a composite of disease, dysfunction, and, ultimately, death) by diet or natural compounds can be defined as dietary geroprotection. While there is no single reliable biomarker to judge the effects of dietary geroprotection, biomarker signatures based on omics (epigenetics, gene expression, microbiome composition) are promising candidates. Recently, omic biomarkers started to supplement established clinical ones such as lipid profiles and inflammatory cytokines. In this review, we focus on human data. We first summarize the current take on genetic biomarkers based on epidemiological studies. However, most of the remaining biomarkers that we describe, whether omics-based or clinical, are related to intervention studies. Then, because of their promising potential in the context of dietary geroprotection, we focus on the effects of berry-based interventions, which up to now have been mostly described employing clinical markers. We provide an aggregation and tabulation of all the recent systematic reviews and meta-analyses that we could find related to this topic. Finally, we present evidence for the importance of the "nutribiography," that is, the influence that an individual's history of diet and natural compound consumption can have on the effects of dietary geroprotection.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2021.1975638.

Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.

Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.

Targeting aging mechanisms: pharmacological perspectives.

Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.

Statin Intake and All-Cause Mortality among Older Nursing Home Residents.

BACKGROUND: Statins are progressively accepted as being associated with reduced mortality. However, few real-world statin studies have been conducted on statin use in older people and especially the most frail, that is, the nursing home residents. OBJECTIVE: The aim of this study was to evaluate the impact of statin intake in nursing home residents on all-cause mortality. METHOD: This is a cross-sectional study of 1,094 older people residing in 6 nursing homes in Flanders (Belgium) between March 1, 2020 and May 30, 2020. We considered all residents who were taking statins for at least 5 days as statin users. All-cause mortality during the 3 months of data collection was the primary outcome. Propensity score overlap-weighted logistic regression models were applied with age, sex, functional status, diabetes, and cardiac failure/ischemia as potential confounders. RESULTS: 185 out of 1,094 residents were on statin therapy (17%). The statin intake was associated with decreased all-cause mortality: 4% absolute risk reduction; adjusted odds ratio 0.50; CI 0.31-0.81, p = 0.005. CONCLUSIONS: The statin intake was associated with decreased all-cause mortality in older people residing in nursing homes. More in-depth studies investigating the potential geroprotector effect of statins in this population are needed.

Youthful and age-related matreotypes predict drugs promoting longevity.

The identification and validation of drugs that promote health during aging ("geroprotectors") are key to the retardation or prevention of chronic age-related diseases. Here, we found that most of the established pro-longevity compounds shown to extend lifespan in model organisms also alter extracellular matrix gene expression (i.e., matrisome) in human cell lines. To harness this observation, we used age-stratified human transcriptomes to define the age-related matreotype, which represents the matrisome gene expression pattern associated with age. Using a "youthful" matreotype, we screened in silico for geroprotective drug candidates. To validate drug candidates, we developed a novel tool using prolonged collagen expression as a non-invasive and in-vivo surrogate marker for Caenorhabditis elegans longevity. With this reporter, we were able to eliminate false-positive drug candidates and determine the appropriate dose for extending the lifespan of C. elegans. We improved drug uptake for one of our predicted compounds, genistein, and reconciled previous contradictory reports of its effects on longevity. We identified and validated new compounds, tretinoin, chondroitin sulfate, and hyaluronic acid, for their ability to restore age-related decline of collagen homeostasis and increase lifespan. Thus, our innovative drug screening approach-employing extracellular matrix homeostasis-facilitates the discovery of pharmacological interventions promoting healthy aging.

Aspirin as a Potential Geroprotector: Experimental Data and Clinical Evidence.

Aging is a biological process with effects at the molecular, cellular, tissue, organ, system, and organismal levels and is characterized by decline in physical function and higher risks of age-related diseases. The use of anti-aging drugs for disease prevention has become a high priority for science and is a new biomedicine trend. Geroprotectors are compounds which slow aging and increase lifespan of the organism in question. The common painkiller aspirin, a member of the non-steroidal anti-inflammatory drug (NSAID) family, is one of the potential geroprotective agents. Aspirin is often used in treatment of mild to moderate pain. It has anti-inflammatory and anti-pyretic properties and acts as an inhibitor of cyclooxygenase which results in inhibition of prostaglandin. Acetylsalicylic acid as an active compound of aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Aspirin has shown life-extending effects in numerous model organisms. This chapter reviews the evidence for clinical efficacy of aspirin including cardiovascular disease prevention, anti-cancer effects, and improvement of cognitive function. However, there are some limitations of these therapies, including the risk of excessive bleeding. We have also summarized numerous experimental and analytical data that support health and longevity benefits of aspirin treatment by affecting pro-longevity pathways.

Is metformin a geroprotector? A peek into the current clinical and experimental data.

Nowadays we observe a growing scientific interest and need to develop novel research approach that target ageing. Metformin, apart from its proven efectiveness as a glucose-lowering agent, was found to exert multidirectional effects because of its cardioprotective, anti-inflammatory and anti-cancer activity. Recently, metformin has become a subject of interest of many researchers as a promising drug with anti-ageing properties; however, its impact on clinical ageing features is still hypothetical. Nevertheless, results of cellular experiments and animal studies confirm that metformin has advantageous effects on ageing. Additionally, a number of clinical trials prove positive effects of metformin on the prevalence of age-related diseases (ARD), including cardiovascular disease or carcinoma. We have observed a significant advancement in human research since a few randomised clinical trials evaluating the impact of metformin on ageing were launched. Here, we present an investigation on anti-ageing properties of metformin, and provide the explanation of mechanisms and pathways implicated in this function. We also analyse available clinical evidence on healthspan extension, all-cause mortality and ARD. Finally, we discuss currently conducted randiomized clinical trials which aim to explore metformin potential as an anti-ageing drug in humans.