Type 2 diabetes (T2D) is an enormous global medical and economic burden and its prevalence is on the rise with an ever ageing, increasingly obese population. It is a debilitating, chronic disease affecting almost half a billion people worldwide. T2D is often presented as a multimorbid disease cluster as it is a major risk factor for the premature onset of multiple age-related conditions such as chronic kidney disease, stroke, impaired wound healing, infection, depression, cognitive decline, and inflammation. T2D is especially a high-risk factor for cardiovascular mortality and cardiac remodelling, with coronary vessel disease and atherosclerosis being primary reasons for the increased incidence of cardiovascular dysfunction.

T2D is more common in an ageing host and "accelerated ageing" has been proposed as a pathogenic mechanism, including cell ageing leading to a complex phenotype termed senescence. Over the past 30 years, cellular senescence has been identified as a possible trigger of general tissue dysfunction and ageing phenotypes. Senescent cell load is low in young individuals but increases with ageing. When senescent cells accumulate they contribute to tissue dysfunction in the context of ageing and related pathologies. Several studies have shown that senescence accumulates in multiple cardiovascular cell populations and is linked with cardiovascular diseases (CVD) including heart failure (HF).

In T2D, comorbidities including obesity, hypertension, and atherosclerosis all have the ability to increase the number of senescent cells. However, the relationship between T2D and myocardial senescence may be both complex and complementary. The microenvironment of systemic metabolic stress in T2D could be permissive to the development and accumulation of senescent cells. On the other hand, senescent cells may contribute to the cardiac parenchyma dysfunction and comorbidities observed in T2D. Overall, it is likely that these complex interactions might lead to a malicious positive feedback in which systemic metabolic dysfunction in the early stages of T2D leads to immune cell senescence that in turn contributes to the worsening of cardiac function and tissue metabolism, which further increases the formation of senescent cells while decreasing their removal.

The aim of this review is to spark discussion and help generate hypotheses that may link senescence to cardiometabolic complications in T2D. We hypothesize that clearing senescent pro-inflammatory immune cells or targeting the SASP (Senescence-Associated Secretory Phenotype) may present opportunities for the development of revolutionary therapies for diabetic cardiomyopathy and its complications, leading to advances in its treatment and prevention. Furthermore, we review our current understanding of the metabolic remodelling of both heart tissue and senescent immune cells in T2D, and we discuss potentially fundamental mechanisms by which these metabolic responses influence and intersect each other to ultimately determine the prognosis of the myocardial inflammation.

Stem cell senescence has been studied in aging, diseases, adverse drug effects, and as a challenging phenomenon in cell therapy. The most investigated types of these cells are endothelial progenitor cells (EPCs), hematopoietic stem cells (HSCs), and mesenchymal stem cells (MSCs). Other investigated kinds include cardiac progenitor cells (CPCs), myeloblasts, and induced pluripotent stem cells (iPSCs). EPCs are involved in vascular homeostasis and new blood vessel regeneration. The decrease in their functional cell number is associated with aging and atherosclerotic processes. HSCs are involved in blood coagulation, oxygen transportation, and immune system function, so their senescence leads to blood dysfunction. MSCs exist in many tissues, including bone marrow, adipose tissue, the bloodstream, and cord blood. MSCs have high self-renewal capacity and the ability to differentiate into other kinds of cells, such as adipocytes, chondrocytes, and osteoblasts, depending on their host organ. Although adult stem cells appear to be valuable sources for regeneration, they have limited sources, differentiation, and expansion potential. However, differentiated cells can be reprogrammed to iPSCs and then differentiated to desired cell types.

This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. As reviewed in this paper, most of these protective agents increased telomerase activity or decreased oxidative damage via various anti-oxidant mechanisms, which ultimately inhibited cellular senescence. Senescence prevention in the body results in health and longevity. Various medicines inhibit senescence through different mechanisms. As mentioned in this review, 17β-estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents in different kinds of stem cells. Although most of these studies were in vitro, we can consider these agents in cell therapy to increase the shelf life and the functional cell number of donated stem cells before transplantation to achieve more clinical success. Moreover, in vitro studies are the first step towards clinical studies. Although more studies are necessary for clinical application, these reviewed agents have been used in the clinical setting for different purposes for a long time; therefore, we only need to evaluate their systemic anti-senescence effects and effective anti-senescence dosages.

We conclude that off-label use of approved medicines and supplements is a convenient, safe, and economical approach to prevent stem cell senescence both in vitro and in vivo. These agents provide a wide range of options based on targeted cells. Since all of them have passed substantial safety trials, we only need to determine their effective dosage to prevent stem cell senescence. Maybe it seems that heterogeneity of administration, patients, and diseases can make repurposing inefficient and time-consuming. Still, in comparison with discovering new anti-senescence agents, this approach is much more economical and accessible. Moreover, performing retrospective studies for each medicine can address these issues.

Earlier studies of wound healing in spiny mice suggested that the animals had - over the course of their evolution - solved the problem of tissue fibrosis (scarring) after injury. But could they also heal damaged internal organs the same way? To find out, they exposed spiny mice to conditions that are known to cause serious kidney injury. Their studies showed that, although spiny mice suffered the same degree of tissue injury initially, they were nevertheless able to completely heal: they regenerated an apparently healthy kidney with no signs of fibrosis. As expected, other mice treated in the same way progressed to organ failure.

"The dramatic and complete recovery of kidney function over a two-week time course in spiny mice was quite surprising to us. The types of severe injuries we used were chosen because they produce a decisive and rapid loss of kidney function in mice and led to complete organ failure over the same two-week period." To find out how the spiny mice do it, the researchers took a comprehensive look at the genes they express. Their studies suggest that the spiny mouse genome is poised at the time of injury to launch a rapid, scarless regenerative response in surviving kidney cells. The analysis uncovered differences in the activity of 843 genes in six unique clusters. Researchers also saw a delayed response by immune cells called macrophages, which are known to play a role in fibrosis. Unlike in other mice, macrophages didn't appear on the scene for about a week.

Fibrosis-driven solid organ failure is an enormous burden on global health. Spiny mice are terrestrial mammals that can regenerate severe skin wounds without scars to avoid predation. Whether spiny mice also regenerate internal organ injuries is unknown. Here, we show that despite equivalent acute obstructive or ischemic kidney injury, spiny mice fully regenerate nephron structure and organ function without fibrosis, whereas C57Bl/6 or CD1 mice progress to complete organ failure with extensive renal fibrosis. Two mechanisms for vertebrate regeneration have been proposed that emphasize either extrinsic (pro-regenerative macrophages) or intrinsic (surviving cells of the organ itself) controls. Comparative transcriptome analysis revealed that the spiny mouse genome appears poised at the time of injury to initiate regeneration by surviving kidney cells, whereas macrophage accumulation was not detected until about day 7. Thus, we provide evidence for rapid activation of a gene expression signature for regenerative wound healing in the spiny mouse kidney.

Evidence suggests that people who abstain from alcohol have a higher mortality rate than those who drink low to moderate amounts. However, little is known about factors that might be causal for this finding. The objective was to analyze former alcohol or drug use disorders, risky drinking, tobacco smoking, and fair to poor health among persons who reported abstinence from alcohol drinking in the last 12 months before baseline in relation to total, cardiovascular, and cancer mortality 20 years later. A sample of residents aged 18 to 64 years had been drawn at random among the general population in northern Germany and a standardized interview conducted in the years 1996 to 1997. The baseline assessment included 4,093 persons (70.2% of those who had been eligible). Vital status and death certificate data were retrieved in the years 2017 and 2018.

We found that among the alcohol-abstinent study participants at baseline (447), there were 405 (90.60%) former alcohol consumers. Of the abstainers, 322 (72.04%) had met one or more criteria for former alcohol or drug dependence or abuse, alcohol risky drinking, or had tried to cut down or to stop drinking, were daily smokers, or self-rated their health as fair to poor. Among the abstainers with one or more of these risk factors, 114 (35.40%) had an alcohol use disorder or risky alcohol consumption in their history. Another 161 (50.00%) did not have such an alcohol-related risk but were daily smokers. The 322 alcohol-abstinent study participants with one or more of the risk factors had a shorter time to death than those with low to moderate alcohol consumption.

The Cox proportional hazard ratio (HR) was 2.44 for persons who had one or more criteria for an alcohol or drug use disorder fulfilled in their history and after adjustment for age and sex. The 125 alcohol-abstinent persons without these risk factors (27.96% of the abstainers) did not show a statistically significant difference from low to moderate alcohol consumers in total, cardiovascular, and cancer mortality. Those who had stayed alcohol abstinent throughout their life before (42; 9.40% of the alcohol-abstinent study participants at baseline) had an HR 1.64 compared to low to moderate alcohol consumers after adjustment for age, sex, and tobacco smoking.

The majority of the alcohol abstainers at baseline were former alcohol consumers and had risk factors that increased the likelihood of early death. Former alcohol use disorders, risky alcohol drinking, ever having smoked tobacco daily, and fair to poor health were associated with early death among alcohol abstainers. Those without an obvious history of these risk factors had a life expectancy similar to that of low to moderate alcohol consumers. The findings speak against recommendations to drink alcohol for health reasons.

The ability of an organism to survive in a specific ecosystem as a result of changes to its behavioral, physiological, morphological, and genetic response is called adaptation. Ecological adaptation strongly underlies lifespan extension in lineages and species where longevity has been observed despite differences in species ecosystem, morphology, and complexity. Predictably, all long-lived species have low extrinsic mortality due to the nature of their habitat or have evolved mechanisms to evade predators and imminent dangers. However, as much as this ability is expected to contribute to lowering extrinsic mortality, it neither explains the variation observed in lifespan or mechanisms through which lifespan is regulated.

Long-lived species are now known to exhibit efficient adaptive responses in essential pathways that contribute to lifespan with evidence of enhanced genome maintenance, DNA damage response, and repair attributing to their longevity. Thanks to affordable genome sequencing, the availability of genome data revealed widespread adaptation in the genomes of long-lived species where positive selection, rare sequence variants, and genome duplication contributed to ecological adaptation, the evolution of body size, and disease resistance. Although mechanisms of extended lifespan of these species are currently unclear, emerging evidence from genomic analyses points to the important role of species adaptation in longevity.

Although there are a number of genetic adaptions in the wild that contribute to lifespan extension, population genetics postulates that genetic changes are hardly to be fixed if such genetic changes do not increase fitness during long-term evolution. Nevertheless, we posit that strong selection acts to maintain these changes, leading to long lifespans in living organisms. We propose that extended lifespan is not by itself under selection but rather an epiphenomenon (by-product) of species adaptation, a phenomenon we have termed here the adaptive hitchhike model. First, the model implies that a new pleiotropic mutation, with one of its effects being extended lifespan, could be favored by natural selection due to its advantage to some other trait and therefore becomes fixed. Second, the model also applies to new pro-longevity mutations that occur at sites closely (or functionally) linked with the allelic sites under selection; if a new pro-longevity mutation arises at a site that is linked to an adapted genome region, natural selection may cause an increase in allele frequency and fix this pro-longevity mutation through linkage and allelic associations.

Therefore, the adaptive-hitchhike model suggests that the selective constraint acting on the genomic region associated with adaptation and fitness is largely responsible for non-random beneficial pro-longevity effects. For example, patterns of selective sweep across loci of close proximities were reported for adaptation to altitude among the Tibetan population, and a further association was found between longevity and hypoxia response in this same population. In other cases, natural selection might act on an already existing but neutral mutation through a sweeping selection; therefore, if neutral alleles responsible for lifespan extension are close enough to other alleles under selection, the chances of recombination are slim, and together, they become fixed in the population.

This model could be mainly summarized in the following ways: (1) Some adaptive genetic changes could have dual functions, i.e., adaptive and longevity effects. (2) A pro-longevity mutation could come under selection and become fixed through direct selection or linkage and allelic association. (3) In the same way that a pro-longevity mutation could become fixed, a geronic (pro-aging) mutation could also become fixed and lead to a shorter lifespan. (4) In the case where environmental pressure is relaxed, pro-longevity effects may be lost. Therefore, our adaptive-hitchhike model of longevity of animals could be tested by (a) identifying pro-longevity effects of genetic changes that respond to adaptation and (b) detecting signals of linkage disequilibrium between adaptive and longevity variations. The novelty of this model is that it gives a key role to such nucleotide substitutions and loci with dual functions. Functional evaluation and validation of adaptive nucleotide substitutions with the pro-longevity potential could provide answers to the century-long questions surrounding the evolvability of animal lifespan.

Calorie restriction (CR) is without a doubt the most robust non-pharmacological intervention against induced and spontaneous cancers. Numerous studies have shown the ability of daily CR to delay neoplasia in multiple tissues and inhibit the growth of chemically induced and spontaneous tumors, including breast cancer. Despite the far-reaching improvements in health and reduction in cancer incidence associated with daily CR, its long-term implementation is not a feasible approach for most humans.

Implementation of protocols that involve intermittent fasting (IF) as clinically viable alternatives to daily CR has been shown to promote similar improvements in metabolic markers and provide protection against cancer growth. However, it is unclear whether optimization of diet composition in these less stringent feeding regimens would provide equal or better protection against tumor growth as daily CR. In this work, we begin to address this knowledge gap by directly assessing the effects of cycles of fasting-mimicking diet (FMD) vs. daily CR.

Using a breast cancer model in mice, we compare the potency of daily CR to that of periodic caloric cycling on FMD or an isocaloric standard laboratory chow against primary tumor growth and metastatic burden. Here, we report that daily CR provides greater protection against tumor growth and metastasis to the lung, which may be in part due to the unique immune signature observed with daily CR. Earlier work has suggested that upregulation of immune-fighting T-cells, specifically CD8+ and CD4+, leads to slower tumor growth and is a good indicator of survival outcome. Conversely, depletion of CD8+ partially eliminates CR-mediated delay in tumor growth. Here, our findings show that daily CR led to an increase in CD8+ and CD4+ cells in peripheral tissues. This is a key observation because T cell exhaustion is one of the major drivers of tumor progression and is indicative of poor prognosis in breast cancer patients.

DNA damage profoundly affects the inflammatory microenvironment where stem cells reside, which can have detrimental consequences for their maintenance and long-term function. Indeed, it has been shown that DNA damage-induced immunostimulatory events can lead to tissue-specific stem cell exhaustion leading to degenerative conditions. Conversely, the release of specific cytokines can also positively impact tissue-specific stem cell plasticity and regeneration of damaged tissues in addition to enhance cancer stem cell activity leading to tumor progression.

This review provides an overview of the main biological mechanisms linked to changes in the stem cell microenvironment and activation of immune processes upon DNA damage induction. Although recent findings have brought to light new insights into these DNA damage-related inflammatory events, some questions remain unanswered. For instance, it is still not clear how to exploit the production of inflammatory cytokines in order to promote on one side immunostimulatory responses against the tumor and on the other side immunosuppressive responses against aging-related degenerative conditions. Especially since the activation of DNA and RNA sensors might change depending on the specific stimulus and cell type.

DNA damage-induced senescence plays a pivotal role in cell cycle arrest and can be used as a barrier against tumor expansion; however, due to the accompanying senescence-associated secretory phenotype (SASP), it is also responsible for loss of tissue function, aging-related diseases and tumor progression. Therefore, further studies are required to understand how to properly modulate the exposure to SASP factors toward the promotion of a regenerative state and against detrimental effects, such as paracrine senescence of neighboring cells and chronic inflammation. Furthermore, it would be interesting to explore how different types of DNA damage can influence senescence and its SASP phenotype in different adult stem cells.

Further understanding of DNA damage immunomodulatory mechanisms, cell- and stimulus-specific variability might unravel novel strategies to regulate the stem cell microenvironment. As mentioned in this review, genotoxic stress can affect the stem cell microenvironment leading to stem cell exhaustion, likely through a combination of a decline in cell number and functional capacity, with the emergence of aging-related pathologies. On the other hand, due to their self-renewal properties, cancer stem cells are also affected by DNA damage and the associated inflammatory microenvironment, which can worsen tumor control and treatment efficacy. Understanding the mechanistic links between stem cell properties and microenvironmental changes initiated upon DNA damage will be critical to counteract the functional decline of adult stem cells in aging-related diseases and effectively diminish cancer stem cell activity and expansion.

As the population ages, frailty syndrome will bring a huge medical burden to society. Previous studies have suggested that gut microbiota imbalance may be a cause of frailty. Animal models and a few human studies have demonstrated that individuals with frailty tend to have increased levels of inflammatory factors (e.g. IL-6, C-reactive protein, and TNF-α) and a chronic inflammatory status. Inflammatory factors have been demonstrated to directly or indirectly reduce key indicators of frailty, such as muscle mass and grip. In addition, gut microbiota imbalance has been demonstrated to be associated with higher expression of inflammatory factors.

Studies have suggested that gut microbiota imbalance leads to enhanced intestinal permeability. This in turn triggers the entry of pathogen-related antibodies like PAMP and DAMP to the circulatory system to subsequently trigger an inflammatory reaction. As a result, investigators believe that the chronic inflammatory status due to gut microbiota imbalance could directly or indirectly give rise to the typical symptoms of frailty (by causing cardiovascular diseases or damaging the musculoskeletal system). In addition, higher levels of inflammatory factors due to gut microbiota may further influence the nervous system of the host via the gut-brain axis to induce neuroinflammation leading to neurodegenerative diseases, i.e., dyskinesia and/or cognitive disorders in patients with frailty.

However, the above assumptions have not been validated in large cohort-based studies. The relationship of gut microbiota imbalance, chronic inflammation, and frailty is not unilateral but complicated and interrelated. Several studies have suggested that chronic inflammation due to gut microbiota imbalance may not be the only cause of frailty. It is worth noting that individuals with frailty are on long-term medication due to preexisting chronic diseases. It has been demonstrated that medications could alter gut microbiome composition. Hence, future studies are necessary to determine whether gut microbiota is a cause of frailty or a result of long-term medication in people with frailty. In addition, factors that may affect the gut microbiota, such as lifestyle, diet, and other health complications, need to be considered comprehensively.

In the coming decades, the proportion of older adults in the world will nearly double. Older adults are a heterogeneous population, with many people over the age of 80 continuing to work and travel, while others might be weak, chronically ill, or disabled. A traditional framework for describing different populations of older adults is "young-old," "old," "old-old," and/or "oldest old". Fried's frailty phenotype is a similar three-stage framework in which people are classified as non-frail, prefrail, or frail. Proteomic analysis finds large changes in gene expression at about the age of 40, 60, and 80. However, these frameworks are not adequate to describe the different stages of aging and subpopulations of older adults. Older age is a risk factor not only for normative physiological changes with aging but also for cancer, heart disease, diabetes, dementia, and many other chronic conditions. Genes, disease, and behaviors can pull on the chronological age of a person and make the person appear younger or older with the risk profile ("biological age") of someone younger or older.

Aging can be viewed as a very slow step-wise decline from wellness and independence toward disability, reduced quality of life, and ultimately death. The rhythm of decline of an individual is very personal and depends on the genes, lifestyle, diseases, and geriatric syndromes such as dementia and falls. The biological causes for physiological changes with aging and for the prevalence of age-associated diseases continue to be explored and debated. Dividing the process of aging into phases, and characterization of these phases from various aspects can raise awareness and recognition that old age is not homogeneous or stereotypical as it is often considered. Healthy, active people in their 70's should not be treated like disabled people in their 90's, and active people in their 90's should not be treated like sick, disabled people in their 90's.

Adults in stages one and two of aging (age 60-79) typically remain in the first stage of the four-phase functional scale. The rate of decline to the next phases depends on vascular risk factors, genetics (family history), and social/environmental factors (such as education, career, physical activity, and social engagement or isolation). The goal of medicine is to compress morbidity, allowing old and old-old adults to spend more time in these earlier functional aging phases and less time in the disabled or burdened phase with bothersome symptoms.

Chronological age stratifications may not correlate with medical, functional, emotional, and social changes that an individual may be experiencing for multiple reasons. The chronological age strata used in this study are obviously inexact, but useful. As noted, older adults are heterogeneous and may develop problems earlier than average or later or never. The final chronological age strata in this proposed staging system are older than 85. In fact, there may be substantial differences between 87-year-olds and centenarians. However, at this time, there is insufficient data to describe organ system changes and disease epidemiology in subpopulations like centenarians. With the advancement of modern medicine and with improved preventive care and lower rates of infectious disease, we more often witness an expanding gap between chronological age and biological age. Some people with advanced age have functional and cognitive abilities that are greater than those of younger people.

Alzheimer's disease (AD) is the most common form of neurodegenerative disease in elder population worldwide. AD is clinically characterized as cognitive decline and psychiatric manifestations. The pathological hallmarks of AD brain are the accumulation of extracellular β-amyloid (Aβ) (senile plaques) and the intracellular twisted strands of the hyper-phosphorylated tau protein (neurofibrillary tangles). These changes in the brain are accompanied by the neuronal damage.

AD is a progressive neurodegenerative disorder that can start decades before the appearance of clinical symptoms. Although several pathological mechanisms of AD have been identified, no satisfactorily effective therapeutics has been developed. Recently, cerebrovascular dysfunctions, as a possible cause in the development and progression of sporadic AD, have gained increasing attention. Increasing evidence has indicated the involvement of various alterations in cerebrovascular structure or functions, such as the cerebrovascular microstructure, blood-brain barrier (BBB) integrity, composition of neurovascular unit, cerebrovascular reactivity and cerebral blood flow, in AD pathophysiology and cognitive defects.

Recent findings further highlighted the prevalence of cerebrovascular disorders in Down syndrome patients and added to a growing body of evidence implicating cerebrovascular abnormalities as a core feature of AD rather than a simple comorbidity. Moreover, adrenergic system, including adrenergic receptors and their downstream molecular signaling process, might serve as the key approach to modulate these cerebrovascular abnormalities and progressive neurodegeneration.

Previous studies have shown that long-term light or moderate fasting such as intermittent fasting can improve health and prolong lifespan. However, in humans short-term intensive fasting, a complete water-only fasting has little been studied. Here, we used multi-omics tools to evaluate the impact of short-term intensive fasting on immune function by comparison of the CD45+ leukocytes from the fasting subjects before and after 72 hour fasting. Transcriptomic and proteomic profiling of CD45+ leukocytes revealed extensive expression changes, marked by higher gene upregulation than downregulation after fasting. Functional enrichment of differentially expressed genes and proteins exposed several pathways critical to metabolic and immune cell functions.

Specifically, short-term intensive fasting enhanced autophagy levels through upregulation of key members involved in the upstream signals and within the autophagy machinery, whereas apoptosis was reduced by down-turning of apoptotic gene expression, thereby increasing the leukocyte viability. When focusing on specific leukocyte populations, peripheral neutrophils are noticeably increased by short-term intensive fasting. Finally, proteomic analysis of leukocytes showed that short-term intensive fasting not only increased neutrophil degranulation, but also increased cytokine secretion. Our results suggest that short-term intensive fasting boost immune function, in particular innate immune function, at least in part by remodeling leukocytes expression profile.

Diabetes mellitus is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. It is associated with the development of secondary complications resulting in several comorbidities. Recent studies have revealed an increased risk of developing cognitive dysfunction or dementia in diabetes patients. Diabetes mellitus is considered a risk factor for many neurodegenerative diseases, including Alzheimer's disease (AD). There is increasing evidence to support a link between diabetes mellitus and AD. Studies have shown the dysfunction of insulin signaling in the brain, resulting in increased tau protein phosphorylation (hyperphosphorylation), a hallmark and biomarker of AD pathology, leading to accumulation of neurofibrillary tangles.

In diabetes mellitus, the insulin dysfunction in the brain is reported to alter the glycogen synthase kinase-3β (GSK-3β) activity showing to enhance tau phosphorylation. In diabetes mellitus and AD, GSK-3β signaling has been involved in the physiological and pathological processes, respectively. This potentially explains why diabetes mellitus patients have an increased risk of developing AD with disease progression and aging.

Interestingly, several in vivo studies with oral antidiabetic drugs and insulin treatment in diabetes mellitus have improved cognitive function and decreased tau hyperphosphorylation. This article will review the relationship between diabetes mellitus and AD as it relates to tau pathology. More understanding of the link between diabetes mellitus and AD could change the approach researchers and clinicians take toward both diseases, potentially leading to new treatments and preventative strategies in the future.

Progressive deterioration in the regenerative potential of stem cells is a hallmark of aging, which results in the failure to maintain proper tissue homeostasis. Hair follicles are independent autonomous stem cell niches and undergo continuous regenerative cycling during their lifespan. With aging, hair follicle have diminished self-renewing capacity, manifesting as cycling defects and poor responsiveness to activating stimuli. hair follicle cycling slows down with aging and gradually turns into senescent alopecia.

Hair follicle stem cells are extensively reprogrammed by the aging process, manifesting as diminished self-renewal and delayed responsiveness to activating cues, orchestrated by both intrinsic microenvironmental and extrinsic macroenvironmental regulators. Dermal white adipose tissue (dWAT) is one of the peripheral tissues directly adjacent to hair follicles and acts as a critical macroenvironmental niche. dWAT directly contributes to hair follicle aging by paracrine signal secretion. However, the altered interrelationship between dWAT and hair follicle with aging has not been thoroughly understood.

Here, through microdissection, we separated dWAT from the skin of aged mice (18 months) and young mice (2 months) in telogen and depilation-induced anagen for transcriptome comparing. Notably, compared with young dWAT, aberrant inflammatory regulators were recapitulated in aging dWAT in telogen, including substantial overexpressed inflammatory cytokines, matrix metalloproteinases, and prostaglandin members. Nonetheless, with anagen initiation, inflammation programs were mostly abolished in aging dWAT, and instead of which, impaired collagen biosynthesis, angiogenesis, and melanin synthesis were identified. Furthermore, we confirmed the inhibitory effect on hair growth of CXCL1, one of the most significantly upregulated inflammation cytokines in aging dWAT.

Finally, we proved that relieving inflammation of aging dWAT by injecting high-level veratric acid stimulated hair follicle regenerative behavior in aged mice. Concomitantly, significantly decreased TNF-a, CCL2, IL-5, CSF2, and increased IL10 in dWAT was identified. Overall, the results elaborated on the complex physiological cycling changes of dWAT during aging, providing a basis for the potential regulatory effect of dWAT on aging hair follicles.

Researchers have recently shown how inflammatory reactions can be resolved by changes to the metabolism of macrophages. Danger signals released by damaged cells during inflammation play a role during this process. 'Rewiring' the mitochondria in the macrophages protects them against overloading and can thus improve the way in which parts of damaged cells are eliminated and resolve the inflammatory reaction. Inflammation is a natural and vital response of our immune system to danger signals and tissue damage. Inflammatory processes help the body to eliminate the triggers, for example bacteria, and to initiate repair mechanisms. Terminating this inflammatory reaction quickly and in a coordinated manner is just as important, however, as otherwise there is a risk of developing chronic inflammatory conditions.

Researchers investigated the function of macrophages at the site where inflammation occurs. These cells are capable of ingesting large quantities of cellular waste and digesting and eliminating the molecular components of this waste in their mitochondria, also referred to as the powerhouse of the cell. The scientists were able to demonstrate that the danger signal interleukin 33, which is released from damaged cells, triggers lasting changes to the metabolism of macrophages, so that their waste disposal capacity significantly increases.

The sheer quantity of waste produced during the inflammatory reaction places the mitochondria under severe strain, and they produce increased quantities of damaging oxygen radicals as a result. Interleukin 33 regulates the function of the mitochondria by initiating a process known as uncoupling in these cell components and protecting them from overloading. "This enables the macrophages to 'let off steam' and carry on ingesting waste without interruption despite the heavy strain placed upon them, resolving the inflammation processes as a result. It may be possible to accelerate and support the resolution of inflammatory processes in the long term by influencing the cell metabolism of the macrophages and deliberately uncoupling their mitochondria."

Hearing loss is not only a physical and financial burden in social life, but also causes psychological problems and psychiatric disorders, including cognitive decline and depression. Genetic alterations, noise, ototoxic drugs, and aging can all contribute to hearing loss. Although the causes vary, the most common causes of deafness are damage or loss of hair cells (HCs) and degeneration of spiral ganglion neurons (SGNs). HCs are responsible for converting external sound signals into electrical signals that are transmitted to the brainstem through SGNs. Recent studies have shown that these sensory cells cannot spontaneously regenerate in adult mammals, so damage or loss of HCs and degeneration of SGNs can result in permanent deafness.

Autophagy is responsible for normal cell survival and homeostasis. A variety of human conditions, such as neurodegenerative diseases, cancer, and inflammation, have been reported to be associated with dysregulated autophagic processes. In the inner ear, many studies have shown that autophagy played an important role in cell development, differentiation, and survival, and recently there has been renewed interest in regulating autophagy to prevent sensorineural hearing loss (SNHL).

Noise and ototoxic drugs increased the levels of oxidative stress in HCs, which contributed to cell death, and in a mouse model that was exposed to noise, the level of autophagy was increased in HCs. It is worth noting that the oxidative stress level in response to noise was dose dependent, and moderate noise induced temporary threshold shifts and increased the level of autophagy in outer hair cells, while severe noise produced excess reactive oxygen species (ROS) that induced permanent threshold shifts. Increasing autophagy with rapamycin can reduce the accumulation of ROS and prevent cell death from noise exposure. In contrast, blocking autophagy via pharmacological or genetic means can increase the accumulation of ROS and promote cell death.

Presbycusis (age-related hearing loss) is a common sensory disorder associated with aging. The level of autophagy decreases with age, and the upregulation of autophagy can promote aging HC survival and slow the degeneration of auditory cells. Though we have known that some proteins and miRNAs participate in the autophagic pathways involved in SNHL making them potential targets for treatment of SNHL, the specific signaling pathways they participate in remain unclear, let alone the known connections between these proteins and miRNAs. The application of autophagy as a treatment for deafness is still a long way off. Current research has been limited to cell lines, explants, and animals, and few clinical trials have examined the role of autophagy. Given the complexity of mechanisms and functions of autophagy, the safest and most effective strategies must be studied in future research.