Fight Aging! Newsletter, March 27th 2023

Clonal hematopoiesis (CH), where hematopoietic stem and progenitor cell (HSPC) clones and their progeny expand in the circulating blood cell population, occurs following the acquisition of somatic driver mutations. Individuals diagnosed with clonal hematopoiesis of indeterminate potential (CHIP) carry somatic mutations in hematological malignancy-associated driver genes, historically at or above a variant allele frequency of 2%, but do not exhibit abnormal blood cell counts or any other symptoms of hematologic disease. However, CHIP is associated with moderately increased risk of hematological cancer, and a greater likelihood of cardiovascular disease and pulmonary disease.

Recent advances in the resolution of high-throughput sequencing experiments suggest CHIP is much more prevalent in the population than once thought, particularly among those aged 60 and over. While CHIP does elevate the risk of eventual hematological malignancy, only one in ten individuals with CHIP will receive such a diagnosis; the problem lies in the continued difficulty in accurately separating the 10% of CHIP patients who are most likely to be in a pre-malignant state from those who are not, given the heterogeneity of this condition and the etiology of the associated hematological cancers. Concerns over the risk of eventual malignancies must be balanced with growing recognition of CH as common age-dependent occurrence, and efforts to better characterize and differentiate oncogenic clonal expansion from that which is much more benign.

In this review, we discuss evolutionary dynamics of CH and CHIP, the relationship of CH to aging and inflammation, and the role of the epigenome in promoting potentially pathogenic or benign cellular trajectories. We outline molecular mechanisms that may contribute to heterogeneity in the etiology of CHIP and incidence of malignant disease among individuals. Finally, we discuss epigenetic markers and modifications for CHIP detection and monitoring with potential for translational applications and clinical utility in the near future.

Recently, our lab and others have utilized senolytics to examine the contribution of senescent cells to impaired muscle adaptability with age, including regeneration following injury and the anabolic response to mechanical overload, as well as any potential role in sarcopenia. There is little evidence that senescent cells are present in aged muscle causing sarcopenia, but they appear to contribute to the impaired ability of muscle to adapt to exogenous stimuli. Even so, systemic deletion of senescent cells improves physical function and has been implicated in slowing sarcopenia. This apparent disconnect between a lack of senescent cells in muscle and improvements in age-associated conditions could be due to various technical or biological reasons.

Work from our lab shows that seven days following muscle injury, there are approximately 250 times more senescence-associated β-galactosidase positive (SA β-Gal+) cells in injured muscle compared to uninjured in both young and old mice. In young mice, these numbers return close to baseline after 28 days, however, the senescent cell burden remains elevated in old mice. Treating mice with a senolytic cocktail of dasatinib and quercetin (D+Q) lowers the senescence burden in old mice, while subsequently reducing the inflammatory profile of the muscle and improving the regenerative response.

β-Gal+ cells appear to transition to senescence in muscle from old mice, developing a senescence-associated secretory phenotype (SASP) relative to cells isolated from young mice 14 days post injury. Some of these findings were recently confirmed by other researchers, who show a greater abundance of senescent cells early in the regenerative process that is reduced over time and greater in old versus young mice. They also show a reduction in senescent cell abundance in response to D+Q treatment following injury, associated with improved regeneration and improvements in muscle force production.

It is important to note that our work shows young mice treated with D+Q display an attenuated regenerative response, whereas others shows an improvement in the regenerative response of young mice as early as 7 days post injury. Considering senescence has been shown to be required for the full regenerative response in skeletal muscle, the large overlap in phenotype between β-Gal+ non-senescent macrophages and bona fide senescent cells likely contributes to the confusion and warrants further investigation.

In a model of muscle hypertrophy, old mice display a blunted hypertrophic response relative to young mice, which is accompanied by a greater senescent cell burden. Treatment with D+Q improves the hypertrophic response in old mice, in addition to lowering the abundance of senescent cells. In this model, we did not observe any change in many of the SASP genes, although genes that are crucial for extracellular matrix reorganization, along with genes that negatively regulate myostatin, were elevated. In summary, senolytics effectively lower the protracted senescent cell burden that accompanies a regenerative or hypertrophic stimulus in muscle from aged mice, resulting in increased muscle fiber size.

Periodontitis is a chronic inflammatory disease characterized by periodontal tissue destruction with loss of tooth-supportive bone. It is thought to be the most common infectious disease and affects more than 40% of people aged over 30 years. Colonization of dental biofilm involving periodontopathic bacteria can trigger inflammation and excessive immune responses that exacerbate breakdown of periodontal tissue. In addition to bactericidal pathogens, various environmental factors affect the pathology and progression of periodontal disease. In particular, aging has been recognized as a major risk factor that affects the onset and severity of periodontitis. Thus, understanding the biological mechanisms that regulate periodontal tissue and health by aging is an urgent issue to establish preventive protocols or specialized therapies for elderly persons in the field of periodontal medicine.

Cellular senescence is a major hallmark of senescence in organs and the whole body. Accumulated senescent cells in aged organs and tissues induce senescence of the body. A large number of studies have indicated that senescent cells secrete various proteins such as proinflammatory cytokines, chemokines, growth factors, and metalloproteinases, termed SASP (senescence-associated secretory phenotype). Therefore, understanding cellular senescence is required to develop more effective therapies and prevention protocols for age-dependent, lifestyle-related diseases. However, whether and how cell types within periodontal tissue undergo cellular senescence with SASP have not yet been clarified.

Recently, it has become evident that cellular senescence is a cause of chronic diseases through production of the SASP. In this study, we examined the pathological roles of cellular senescence in periodontitis. We found localization of senescent cells in periodontal tissue, particularly the periodontal ligament (PDL), in aged mice. Senescent human PDL (HPDL) cells showed irreversible cell cycle arrest and SASP-like phenotypes in vitro. Additionally, we observed age-dependent upregulation of miR-34a in HPDL cells. These results suggest that chronic periodontitis is mediated by senescent PDL cells that exacerbate inflammation and destruction of periodontal tissues through production of SASP proteins. Thus, miR-34a and senescent PDL cells might be promising therapeutic targets for periodontitis in elderly people.

The blood-brain barrier (BBB) is a dynamic interface that regulates the cellular communication between neural tissues and the blood and its constituents. It acts as a selective semipermeable barrier that controls the transport of substances to and from the central nervous system, serving as a key player in neural homeostasis. The blood is separated from central nervous system (CNS) by brain endothelial cells separated by tight junctions, adherens junctions, and gap junctions; pericytes; the foot processes of astrocytes, and the basement membrane composed of extracellular matrix components. Two main transport pathways occur within BBB: transcellular via endothelial cell used by the vast majority of the molecules which can be active (dependent on energy) or passive; and paracellular via passive diffusion through tight junctions.

The ubiquity and importance of BBB in CNS physiology also translate to how it is also impaired in almost every neurological condition. Such is the case of the most common cause of dementia, Alzheimer's disease (AD). AD affects more than 30 million people worldwide, a number that is expected to increase dramatically in the foreseeable future. To date, intracellular hyper-phosphorylated tau protein accumulation (neurofibrillary tangles) and extracellular amyloid-β (Aβ) deposition (senile plaques) in brain parenchyma is considered the central neuropathological hallmarks of the disease. However, pathogenesis is still not fully understood, and it is unclear whether these protein abnormalities are causative or rather incidental changes in the disease. Nevertheless, it is generally accepted that both proteins play a key role in disease pathogenesis with Aβ acting upstream of tau with other hypotheses building on and extending this to explain other aspects of the disease.

Aβ deposition seems to be a critical pathological trigger in AD and disruption of BBB leads to increased vascular permeability, allowing the entrance and/or hampering the clearance of toxic molecules that can trigger inflammatory and immune responses and, ultimately, neurodegeneration. One such pathologic protein whose normal clearance is dependent on a healthy BBB is the 42 amino acid Aβ peptide (Aβ42), considered the major toxic Aβ in AD. Not surprisingly, BBB dysfunction leads to Aβ deposition by disrupting its transporters. Moreover, there is experimental evidence that a disrupted BBB promotes its production from the amyloid precursor protein (APP) through the activation of the amyloidogenic pathway where APP is cleaved in sequence by β-secretase and γ-secretase.

Several studies have demonstrated BBB breakdown and dysregulation in AD. Whether it is a cause or consequence of the disease has been a matter of debate. Available evidence points to BBB breakdown as an early event preceding AD pathology. These findings have been supporting the vascular hypothesis of AD. First published in 1993 this hypothesis postulates that neurodegeneration is the consequence of a series of pathogenic pathways originating in blood vessels. More recently, others proposed the two-hit vascular hypothesis of AD. According to this hypothesis, impairment of blood vessels leads to BBB dysfunction and initiates a cascade of events leading to neuronal dysfunction (hit one). BBB dysfunction reduces Aβ clearance and increases its production inducing accumulation of this peptide, amplifying neuronal dysfunction, and accelerating neurodegeneration (hit two).

Blood-brain barrier has been emerging as a central hub for AD pathogenesis, presenting as a potential target to treat AD. Understanding its dysfunctional role in AD pathogenesis would be paramount for AD biology clarification and would probably give insights into other brain disorders. In this review, we will detail pathogenic and therapeutic links between AD and BBB offering a comprehensive and integrative view that includes the genetic landscape of AD and anticipates future research and treatment.

Chronic kidney disease (CKD) is a clinical syndrome secondary to the definitive change in function and structure of the kidney, which is characterized by its irreversibility and slow and progressive evolution. Alzheimer's disease (AD) is characterized by the extracellular accumulation of misfolded β-amyloid (Aβ) proteins into senile plaques and the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau. In the aging population, CKD and AD are growing problems. CKD patients are prone to cognitive decline and AD. However, the connection between CKD and AD is still unclear.

The available evidence suggests that CKD and AD are pathologically related through the renin-angiotensin system (RAS), uremic toxins, and erythropoietin (EPO), which contribute to the occurrence and development of CKD and may aggravate the development of AD. In CKD, excess renin is released and increases circulating angiotensin II (Ang II) levels, resulting in AT1R upregulation and enhancing systemic vascular resistance, increasing blood pressure, and promoting sodium reabsorption in the proximal tubule and (through aldosterone) the collecting duct. In AD animal models, the cerebroventricular infusion of Ang II into aged normal rats increased both tau pathology and amyloid precursor protein (APP) levels, leading to an increase in amyloid-β (Aβ) accumulation. It was also shown that Ang (1-7) expression in the brain increased with disease progression and that there was an inverse correlation between Ang (1-7) level and tau hyperphosphorylation.

In AD model mice, Ang II not only impaired blood-brain barrier (BBB) function in the cerebral microcirculation but also induced inflammatory and thrombotic phenotypes. The binding of Ang II with AT1R damaged the BBB, leading to its leakage and the entry of circulating toxins into the brain. Additionally, AT2R and MasR promoted an M2 anti-inflammatory phenotype in microglia, which is a potential mechanism for alleviating neuronal dysfunction and inflammation and ultimately, for reversing cognition impairment. Based on the current evidence, we propose that the combination of Ang II and AT1R causes BBB leakage and activates microglia to secrete inflammatory factors that lead to apoptosis, neuronal injury, and neurodegeneration, resulting in the aggravation of AD; the activation of the AT2R/MasR axis produces the opposite physiological effect.

It remains unclear whether RAS imbalance in CKD is a cause of AD and vice versa. The following open questions warrant investigation in future studies: (1) Do CKD patients with AD have more severe imbalances in the RAS than those without AD? (2) What are the most significantly altered components of the RAS in CKD patients with AD, and are these components mainly proinflammatory (ACE/AT1R) or anti-inflammatory (ACE2/AT2R/MasR)? (3) Can the use of ACEI/ARB drugs prevent or delay the occurrence of AD? Answering these questions may provide insights that can guide the development of novel treatments for both diseases.

Over the past decade, clinical trials have reported the efficacy of drugs that target cellular senescence and their potential use in the treatment of age-related chronic diseases, such as type 2 diabetes mellitus (T2DM). When normal cells are subjected to severe DNA damage, they either die by apoptosis or undergo irreversible cell proliferation arrest by induction of cellular senescence. These biological defense mechanisms prevent the proliferation of abnormal cells that have suffered DNA damage. Cellular senescence is the state in which cells irreversibly stop proliferating while retaining their metabolic activity and can be induced by external stressors such as aging, obesity, and radiation due to DNA damage, telomere shortening, and mitochondrial dysfunction.

A unique characteristic of senescent cells is the secretion of senescence-associated secretory phenotype (SASP), which induces chronic inflammation through the secretion of inflammatory proteins. The SASP has been involved in the pathogenesis of several age-related diseases, including cancer. Chronic insulin exposure, which occurs in T2DM, has been shown to cause senescence in hepatocytes, pancreatic β-cells, and adipose tissue. Hyperglycemia, pathognomonic of T2DM, can also contribute to senescence through several pathways, and animal studies have shown that removal of senescent cells improves blood glucose levels and decreases diabetic complications.

However, at least two barriers need to be overcome before these therapies can be translated to the clinic: (1) differences between senescent cells in different tissues are unknown, and (2) the specific effects of removing senescent cells in each organ remain to be determined. Therefore, this review focuses on the mechanisms of cellular senescence and its SASP in four key organs for the regulation of blood glucose levels: pancreas, liver, skeletal muscle, and adipocytes, and summarizes ongoing efforts to therapeutically target cellular senescence in them.

Adipose tissue is essential for age-related dysfunction such as metabolic diseases, while aging can also generate multiple effects on adipose tissue, including redistribution of deposits and composition, adipose tissue plasticity reduction, senescent cell accumulation and inflammaging. Among them, adipose tissue inflammation is the most important. This chronic inflammation is usually promoted by senescent cell/dead cell accumulation, adipocyte hypertrophy, free fatty acids (FFAs) and lipopolysaccharide (LPS), and immune cell dysregulation.

Various cellular and molecular mechanisms regulate adipose tissue inflammaging. Immune cells are recruited to adipose tissue by different chemokines, and undergo tremendous changes in both their numbers and characteristics during aging. Proinflammatory signaling pathways, including the JAK/STAT, Wnt/β-catenin, NF-κB, and MAPK signaling pathways, control the process of adipose tissue inflammaging in different way. Indeed, Increased inflammaging in aging impacts adipose tissue, leading to adipose tissue dysfunction and ectopic lipid accumulation, further impacting the overall health status.

Systemic diseases, such as type II diabetes, cardiovascular disease, and cancer, are somewhat caused by adipose tissue inflammation. Since adipose tissue inflammaging plays pivotal roles, emerging anti-aging interventions have recently been developed targeting adipose tissue. In this review, we summarize the latest approaches that can extend healthy lifespan and delay the onset of age-related diseases including caloric restriction, senotherapeutics, immune therapies, and other strategies targeting adipose tissue inflammaging related signaling pathways. Further research may need to focus on whether suppressing the inflammatory response in adipose tissue can reverse the senescent phenotype, an approach that may identify new targets to relieve aging-associated complications.

Age-related decline in cognitive functions is associated with reduced hippocampal neurogenesis caused by changes in the systemic inflammatory milieu. Mesenchymal stem cells (MSC) are known for their immunomodulatory properties. Accordingly, MSC are a leading candidate for cell therapy and can be applied to alleviate inflammatory diseases as well as aging frailty via systemic delivery.

Akin to immune cells, MSC can also polarize into pro-inflammatory MSC (MSC1) and anti-inflammatory MSC (MSC2) following activation of Toll-like receptor 4 (TLR4) and TLR3, respectively. In the present study, we apply pituitary adenylate cyclase-activating peptide (PACAP) to polarize bone-marrow-derived MSC towards an MSC2 phenotype. Indeed, we found that polarized anti-inflammatory MSC were able to reduce the plasma levels of aging related chemokines in aged mice (18-months old) and increased hippocampal neurogenesis, following systemic administration.

Similarly, aged mice treated with polarized MSC displayed improved cognitive function in the Morris water maze and Y-maze assays compared with vehicle- and naïve-MSC-treated mice. Changes in neurogenesis and Y-maze performance were negatively and significantly correlated with sICAM, CCL2, and CCL12 serum levels. We conclude that polarized PACAP-treated MSC present anti-inflammatory properties that can mitigate age-related changes in the systemic inflammatory milieu and, as a result, ameliorate age related cognitive decline.

Accumulation of senescent cells is the prominent risk factor for osteoarthritis (OA), accelerating the progression of OA through a senescence-associated secretory phenotype (SASP). Recent studies emphasized the existence of senescent synoviocytes in OA and the therapeutic effect of removing senescent synoviocytes. Ceria nanoparticles (CeNP) have exhibited therapeutic effects in multiple age-related diseases due to their unique capability of reactive oxygen species (ROS) scavenging. However, the role of CeNP in OA remains unknown.

Our results revealed that CeNP could inhibit the expression of senescence and SASP biomarkers in multiple passaged and hydrogen-peroxide-treated synoviocytes by removing ROS. In vivo, the concentration of ROS in the synovial tissue was remarkably suppressed after the intra-articular injection of CeNP. Likewise, CeNP reduced the expression of senescence and SASP biomarkers as determined by immunohistochemistry analysis. The mechanistic study showed that CeNP inactivated the NFκB pathway in senescent synoviocytes. Finally, safranin O-fast green staining showed milder destruction of articular cartilage in the CeNP-treated group compared with the OA group.

Overall, our study suggested that CeNP attenuated senescence and protected cartilage from degeneration via scavenging ROS and inactivating the NFκB signaling pathway. This study has potentially significant implications in the field of OA as it provides a novel strategy for OA treatment.

The prevalence of heart failure is increasing in aging populations. Furthermore, dementia is more prevalent in patients with heart failure. Dementia is detected 10 years earlier in patients with heart failure in Asian countries, particularly low-income countries, than in Western countries. Heart failure and dementia share similar cardiovascular risk factors, such as age, hypertension, diabetes, dyslipidemia, and increased arterial stiffness, which explains their overlap in elderly patients.

In a large database of patients with heart failure (mean age 75.3 years), 11.0% developed dementia during an average follow-up period of 4.1 years. Heart failure patients with dementia were at a 4.5-fold higher risk of all-cause mortality, 5.4-fold higher risk of cardiovascular death, and 3.8-fold higher risk of noncardiovascular death. An analysis of a longitudinal dataset indicated a causal relationship between decreased cardiac function and cognitive decline.

Heart failure patients with dementia often have sarcopenia and cachexia. Nutritional changes caused by hypoperfusion and edema in skeletal muscles, the intestines, and visceral organs may contribute to the risk of cardiovascular and noncardiovascular mortality. Autonomic nerve dysregulation has been detected in some patients with dementia, particularly those with Lewy body disease. Elderly patients with heart failure are also more susceptible to infections owing to a decreased lymphocyte count.

Heart failure patients that develop dementia enter a vicious cycle of heart failure, dementia, malnutrition, sarcopenia, and cachexia, which is associated with an increased risk of all-cause mortality. Therefore, the prevention of cognitive decline is important in elderly patients with heart failure.

Do we understand how cellular reprogramming improves health and longevity?

There have been two major camps in aging since long ago. One says that aging happens due to damage, to proteins, lipids, RNA, and DNA, and that you have to go in there with your repair kit and fix it as a therapist. The other camp says that it's all epigenetic, and that if you convince the cell that it's young, it will get its own toolkit out and start repairing as much as it can. Some things are beyond repair. If you delete all copies of a tumor suppressor, that's not something a young cell can repair. But most things are fixable with epigenetics - at least, that's how the second hypothesis goes.

I believe in a hybrid model. I think most of the work can be done epigenetically. A surprising amount of it can be done via the bloodstream, but probably not all of it. Then, there's a residual amount that you can fix with the Yamanaka factors and another residual amount that you can fix by restoring genes. Since we do the epigenetic reprogramming by adding in genes, it's not that fundamental a difference between adding in genes that will go into the blood, adding genes that will reprogram the nucleus, and adding genes that are missing, like tumor suppressors. In a certain sense, they are all addressable by multiplex gene therapy. That's why being able to either use multiple rounds of dosing or to have bigger vectors will become increasingly important.

Given the rising popularity of partial reprogramming, what is its overall place in the longevity landscape?

I think there are subtle but important differences between anti-aging drugs and drugs that improve biomarkers in the way that statins improve cholesterol. That doesn't mean such drugs increase longevity, just that they improve this one biochemical. It could actually hurt you; for instance, it could improve cardiovascular chances for some subset of the population, but for another subset, it could hasten muscle pain. So, affecting biomarkers is one thing. Reversing diseases of aging is different. You could do it just by addressing that particular disease, or you could do it more broadly, affecting multiple diseases. You might get FDA approval for one of them, but it's actually affecting multiple ones, and maybe acting preventatively. Say, there might be a cure for muscle wasting that helps prevent a variety of diseases. Finally, you're really at the core of aging when you reprogram shared elements - with good feedback systems that already exist in the body or with feedback systems that you introduce as part of the therapy.

Are you bullish about longevity biotech?

I think the whole field is very healthy economically and scientifically. We have passed through multiple "valleys of death". We're now in the solid science phase, and this field is going to be very impactful, maybe more impactful than any other pharmaceuticals in history, including even antibiotics, because our very ability to fight off diseases is age-related. Almost every single form of human morbidity and mortality has an age-related component to it. If you want to have a pleiotropic effect on many different diseases, this is the way to go.

Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway.

We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia. In this study, we used a triple muscle-specific creatine kinase (tMCK) promoter to restrict NT-3 expression to the skeletal muscle and self-complimentary adeno-associated virus serotype 1 (scAAV1) as vector. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle.

NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves, and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

The classic signs of acute inflammation are redness, heat, pain, swelling, and loss of function. Acute inflammation in the absence of infection can also promote wound regeneration or repair, depending on the severity of the tissue damage. In contrast, the chronic, sterile inflammation that results from repeated immune stimulation over time may be the result of the degeneration of a number of receptors that activate the innate immune system in elderly individuals.

A "generic" inflammatory pathway includes Inducers, Sensors, Mediators and Effectors. An example of this pathway in action would be the stimulation of Sensors, such as the Toll-Like Receptors (TLRs) present on macrophages or mast cells by a microbe (Inducer), leading to the production of cytokines (Mediator), which act on target tissues (Effectors) in order to promote the recruitment of pathogen-destroying cells to the affected area. These actions lead to the signs of inflammation through vasodilation, edema, and the presence of pain-promoting prostaglandins in the affected tissue.

Low-grade inflammation is often observed as part of aging. This phenomenon has been termed "inflammaging". In addition to a general decline in function during aging, the nature of the immune system also changes, in a phenomenon known as immunosenescence. This accounts for the reduced ability of the elderly to respond to antigens and correlates with increased susceptibility to infections. The co-ordination of the many processes that contribute to the effective control of the inflammatory response relating to aging is complicated, and the revelation of the mechanisms underlying this control has only recently begun.

It has been found that the production of the correct inflammatory mediator in a timely manner requires exquisite control at the transcriptional level. Importantly, all eukaryotic transcription takes place in the context of the nucleoprotein complex known as chromatin. In this review, we aim to emphasize the roles of chromatin regulation at the intersection between inflammation, aging, and metabolism to deepen our mechanistic understanding of inflammaging while we discuss the possibility of obtaining control over inflammaging and directions for further studies.

The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline.

We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Hearing loss is mainly considered a sensory disorder in humans. Multiple factors contribute to the pathogenesis of sensorineural hearing loss (SNHL), such as noise exposure, ototoxic drugs, genetic mutations, aging, and chronic conditions. Histopathological changes of SNHL are characterized by mechanosensory hair cell damage, spiral ganglion neuron (SGN) loss, and stria vascularis atrophy. Emerging studies have suggested that mitochondrial DNA damage, reactive oxygen species (ROS) overproduction, and inflammatory mediators activation are associated with subsequent cochlear damage.

Mitochondria ROS could induce inflammasome activation that promotes various disease progression. Moreover, ROS could also induce cellular defense process such as autophagy, a cytoprotective mechanism that delivers damaged organelles to lysosomes for degradation. Current studies reveal autophagy exhibits an antioxidative capacity to protect against hair cell damage and possesses the potential to alleviate noise-induced hearing loss (NIHL). Autophagy not only clears up undesired proteins and damaged mitochondria (mitophagy), but also eliminate excessive ROS. Appropriate enhancement of autophagy can reduce oxidative stress, inhibit cell apoptosis, and protect auditory cells.