Protein aggregation, the abnormal accumulation of misfolded or unfolded proteins, is a ubiquitous phenomenon associated with numerous human pathologies, including neurodegenerative diseases, metabolic disorders, and cancer. These aggregations often lead to cellular dysfunction and, ultimately, tissue damage and organ failure. To combat this threat, cells have evolved intricate mechanisms to maintain protein homeostasis (proteostasis), including the molecular chaperones, ubiquitin-proteasome system (UPS), and autophagy. Among these, autophagy, particularly aggrephagy - a subtype of autophagy specifically targeting protein aggregates - has garnered significant attention due to its pivotal role in the clearing toxic protein aggregates.

Chaperonin Containing TCP-1 (CCT) is a multi-subunit protein complex essential for the folding of approximately 10% of cytosolic proteins. CCT is composed of eight distinct subunits (CCT1-8), each playing a critical role in maintaining the structural integrity of nascent polypeptides. Among these, CCT2, a subunit of CCT, has recently emerged as a novel player in the regulation of aggrephagy, shedding light on the intricate interplay between protein folding and degradation

This mini review outlines CCT2's dual roles: as a molecular chaperone crucial for protein folding and homeostasis, and recently, as an autophagy receptor in aggrephagy, degrading solid protein aggregates to maintain proteostasis. We detail CCT2's mechanisms in aggrephagy, emphasizing its interplay with cellular clearance machinery. The selectivity of CCT2-mediated aggrephagy for solid aggregates has implications for neurodegenerative diseases. Further research is warranted to explore the therapeutic potential of enhancing CCT2-mediated aggrephagy in such diseases.

Increased fall risk caused by vestibular system impairment is a significant problem associated with aging. A vestibule is composed of linear acceleration-sensing otoliths and rotation-sensing semicircular canals. Otoliths, composed of utricle and saccule, detect linear accelerations. Otolithic organs partially play a role in falls due to aging. Aging possibly changes the morphology and functions of otoliths. However, the specific associations between aging and otolith changes remain unknown. Therefore, this study aimed to clarify these associations in mice.

Young C56BL/6N (8 week old) and old (108-117 weeks old) mice were used in a micro-computed tomography (μCT) experiment for morphological analysis and a linear acceleration experiment for functional analysis. Young C56BL/6N (8 week old) and middle-aged (50 week old) mice were used in electron microscopy experiments for morphological analysis. μCT revealed no significant differences in the otolith volume but significant differences in the otolith density between young and old mice. μCT and electron microscopy revealed significant differences in the structure of striola at the center of the otolith. Significant differences were also observed in the amplitude of the eye movement during the vestibulo-ocular reflex induced by linear acceleration, indicating that the otolith function was worse in old mice than in young mice.

This study demonstrated the decline in otolith function with age caused by age-related morphological changes. Specifically, when otolith density decreased, inertial force acting on the hair cells decreased, and when the structure of striola collapsed, the function of cross-striolar inhibition decreased, thereby causing a decline in the overall otolith function.

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases.

Chronic stress and accumulated damage, whether occurring naturally or from acute and chronic infections, can lead to persistent inflammation, a precursor to altered cellular states known as the hallmarks of aging. As we age, our immune systems can aberrantly produce persistent low-grade, chronic, and systemic inflammation in non-pathogenic or "sterile" conditions referred to as "inflammaging". Aged individuals frequently exhibit this pro-inflammatory state characterized by elevated levels of pro-inflammatory markers within cells and tissues. Inflammaging can affect both the innate and adaptive immune responses and multiple molecular mechanisms can drive this inflammation, including cellular senescence, mitochondrial dysfunction, defective autophagy, inflammasome activation, DNA damage, and changes in the microbiome. Inflammaging is theorized to contribute to the development of chronic age-related conditions such as cancer, cardiovascular disease, diabetes, frailty, neurodegeneration, and osteoarthritis.

Immune resilience (IR) is a critical component of fully understanding immunosenescence. Immune resilience refers to the ability of the immune system to maintain or quickly restore its functions, thus promoting disease resistance and controlling inflammation during infectious diseases and other inflammatory stressors. Individuals with immune resilience are likely to have high immunocompetence and functionality, along with minimal background inflammation, which can potentially help buffer against the immune and systemic effects of harmful stimuli. However, reliably capturing this remains elusive. Much of the knowledge in this area is derived from disparate animal studies that lack standardized models, cross-sectional or short-term longitudinal analyses, and have limited endpoints. While previous studies suggest that immune variation is largely driven by non-heritable factors, investigating heritable influences on immunity is still worthwhile and presents an opportunity to identify novel therapeutic targets.

Current studies on immune resilience have been largely limited to basic immunophenotyping of common immune populations, cytokine analyses, or transcriptomic studies on leukocytes. Although cytokine analysis can provide information on the inflammatory background and immunophenotyping can describe population shifts, additional functional studies are needed to properly assess immunocompetence and how it changes in response to age, immune challenges, or other forms of stress. Furthermore, these endpoints need to be accessible, practical, and cost-effective for widespread clinical deployment. These steps are critical for identifying and benchmarking biomarkers or surrogate endpoints for immune resilience that can: 1) be translated back to pre-clinical animal models to generate standardized models with translational potential, and 2) be used to more reliably assess interventions that promote immune resilience and allow for comparisons between them.

The female reproductive system is the first to age in the human body with fertility decreasing for women in their mid-thirties and reproductive function ceasing completely at menopause. In the ovary, aging is associated with a loss in gamete quantity and quality which contributes to infertility, miscarriages, and birth defects. Moreover, the age-dependent loss of the ovarian hormone, estrogen, has adverse general health outcomes. These sequelae are significant as women globally are delaying childbearing and the gap between menopause and lifespan is widening due to medical interventions.

Although aging is a multifaceted process, loss of proteostasis and dysfunctional protein quality control pathways are hallmarks of reproductive aging. The mammalian ovary is comprised of a fixed and nonrenewable pool of long-lived cells or oocytes. In humans, oocytes initiate meiosis during fetal development, and by birth, all oocytes are arrested in the cell cycle. This cell cycle arrest is maintained until ovulation, which occurs any time between puberty and menopause, and thus can span decades. The oocytes are particularly sensitive to protein metabolism alterations because they contribute the bulk cytoplasm to the embryo following fertilization. Thus, maternal proteins produced during oogenesis are essential to generate high-quality gametes.

The ovarian microenvironment is a critical determinant of gamete quality and has been shown to become fibro-inflamed and stiff with age. Although a small number of oocyte-specific proteins have been identified as long-lived, including cohesins and several centromere-specific histones, there has not been a discovery-based approach to define the long-lived proteome of the ovary and oocyte. Thus, the potential contribution of long-lived proteins (LLPs) to the age-related deterioration of the reproductive system in mammals remains to be elucidated. In this study we used multi-generational whole animal metabolic stable isotope labeling and leading mass spectrometry (MS)-based quantitative proteomic approaches to visualize and identify ovarian and oocyte long-lived macromolecules in vivo during milestones relevant to the reproductive system.

LLPs tend to be part of large protein complexes and include histones, nuclear pore complex proteins, lamins, myelin proteins, and mitochondrial proteins. In the ovary, the major categories of LLPs included histones, cytoskeletal proteins, and mitochondrial proteins. Our findings provide a novel framework for how long-lived structures may regulate gamete quality. Long-lived macromolecules localized throughout the ovary including the follicular compartment with prominent signals in the granulosa cells of primordial and primary follicles relative to later stage growing follicles. These findings are consistent with the knowledge that the squamous pre-granulosa cells surrounding the oocyte within primordial follicles form early in development. These squamous granulosa cells are generally thought to lack the ability to undergo mitotic division until follicles are activated to grow, so it is not surprising that we observed long-lived macromolecules persisting within them. Thus, it is possible that these long-lived molecules will accumulate more damage in primordial follicles that remain quiescent for longer periods relative to those that activate earlier. Whether such damage occurs and how it translates into decreased follicle survival or gamete quality will require further investigation.

Within the extrafollicular ovarian environment, the ovarian surface epithelium (OSE) exhibited a striking enrichment of long-lived molecules. The OSE is highly dynamic due to repeated post-ovulation wound healing and repair, and its regenerative capacity occurs through a somatic stem/progenitor cell-mediated process. Interestingly, LLPs are retained in other cells undergoing repeated asymmetric divisions and are speculated to contribute to the reproductive aging process. Consistent with this possibility, the architecture and wound healing ability of the OSE is altered with advanced reproductive age.

Given the potential fundamental function of osteal macrophages in bone pathophysiology, we study here their precise function in experimental osteoporosis. Gene profiling of osteal macrophages from ovariectomized mice demonstrated the upregulation of genes that were involved in oxidative stress, cell senescence, and apoptotic process. Single cell RNA sequencing analysis revealed that osteal macrophages were heterogenously clustered into 6 subsets that expressed proliferative, inflammatory, anti-inflammatory, and efferocytosis gene signatures.

Importantly, postmenopausal mice exhibited a 20-fold increase in the subset that showed a typical gene signature of cell senescence and inflammation. These findings suggest that the decreased production of estrogen due to postmenopause altered the osteal macrophages subsets, resulting in a shift toward cell senescence and inflammatory conditions in the bone microenvironment.

Furthermore, adoptive macrophage transfer onto calvarial bone was performed and mice that received oxidative-stressed macrophages exhibited greater osteolytic lesions than control macrophages, suggesting the role of these cells in development of inflammaging in bone microenvironment. Consistently, depletion of senescent cells and oxidative-stressed macrophages subset alleviated the excessive bone loss in postmenopausal mice. In conclusion, our data provided a new insight into the pathogenesis of osteoporosis and sheds light on a new therapeutic approach for the treatment/prevention of postmenopausal osteoporosis.

Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and white adipose tissue (WAT) function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.

Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.

Although stem cell quiescence and exhaustion in aged tissues share the same property of suppressed proliferation, they are distinct in a sense that quiescent cells, but not exhausted cells, can proliferate upon receiving stresses. Aging-induced stem cell exhaustion occurs in many types of tissue stem cells in mice, including hematopoietic stem cells, intestinal stem cells (ISCs), skeletal muscle stem cells, and hair follicle stem cells. Stem cell exhaustion can occur due to two mechanisms: (1) replicative stress in response to proliferation and (2) mechanisms independent of cell proliferation. The resulting phenotype, proliferation or exhaustion, likely depends on the tug of war competition between conflicting signals.

In Drosophila, ISCs demonstrate a proliferative phenotype during aging. Although PIWI was suggested to suppress Jak-Stat-mediated exhaustion of ISCs, signaling that skews ISCs toward exhaustion during aging is not known. There might be some undiscovered signals that lead cells toward exhaustion. During aging, changes in chromatin structures and gene expression occur simultaneously in tissue stem cells. Changes in chromatin structures may underlie changes of some gene expression. We discovered changes of chromatin accessibility and gene expression that have a propensity to exhaust intestinal stem cells (ISCs). During aging, Trithorax-like (Trl) target genes, ced-6 and ci, close their chromatin structures and decrease their expression in intestinal progenitor cells. Inhibition of Trl, ced-6, or ci exhausts ISCs. This study provides new insight into changes of chromatin accessibility and gene expression that have a potential to exhaust ISCs during aging.

We examined whether physical activity buffers high levels of sitting time on cardiovascular and metabolic health indices of total cholesterol/high-density lipoprotein ratio (TC/HDL) and body mass index (BMI) in a sample of young adults. The expected negative associations of sitting on health indices were apparent in this relatively healthy period of adulthood. However, meeting the current physical activity recommendations did not buffer the impacts of sitting on BMI or TC/HDL fully, although engagement in vigorous physical activity is associated with lower, healthier levels.

For females in their early 30s and males in their late 20s, the TC/HDL is shown to cross into the moderate cardiac risk territory when sitting 8.5 hours per day even after meeting current physical activity recommendations. Performing vigorous physical activity reveals a notable age-equivalent benefit with any level of sitting where an individual exercising 30 minutes of day of vigorous intensity exercise has comparable TC/HDL and BMI values to someone 5 or 10 years younger respectively sitting the same amount of time without any vigorous physical activity. Our findings suggest maintaining sedentary behavior throughout young adulthood may contribute to later cardiovascular and metabolic disease susceptibility.

The co-twin control analyses with the monozygotic pairs further illustrates the importance of additional vigorous physical activity in place of sitting time or in addition to prolonged sitting time to improve one's TC/HDL. Failing to disrupt sedentary behavior could set a course towards poorer health and functioning across the lifespan, particularly since once disease onset occurs for many chronic conditions, disease maintenance will be the primary focus of health intervention instead of recovery. This has been illustrated in previous work implicating elevated BMI and dyslipidemia measurements in early adulthood linked to adverse impacts occurring later in life as they relate to issues such as coronary heart disease, stroke, and other major health issues. Given these links, early intervention of suboptimal BMI and TC/HDL values is critical to prevent a multitude of health-related issues past early adulthood.

It has become increasingly evident that males and females across species show differences in lifespan and ageing. In many mammals, females live longer than males, while in birds, males are the longer-lived sex. In humans, women live on average 5 years longer than men. Paradoxically, women are frailer later in life (usually after the onset of menopause) and do not necessarily have a longer healthspan.

Age-associated illnesses are often sex-biased. For example, in 2018, men older than 65 years showed higher death rates of cancer, heart disease, stroke, and diabetes, while Alzheimer's disease (AD), influenza, and pneumonia showed higher death rates in women. Women are also more susceptible to autoimmunity. Such age-associated sex biases deserve more attention, as the elderly population worldwide is expected to double from 12% to 22% between 2015 and 2050.

One reason why either sex can be more prone to certain age-associated phenotypes are the sex chromosomes. In mammals, females are XX and males XY, where the presence of the Y chromosome triggers the development of male gonads and secondary sexual traits. Mammals share evolutionarily conserved sex chromosomes, but in wild populations, not all mammalian females live longer than males. However, when they do, they have a longer median lifespan of around 20%. How the sex chromosome complement impacts longevity is an active area of research.

Increasing global life expectancy motivates investigations of molecular mechanisms of aging and age-related diseases. This study examines age-associated changes in red blood cells (RBCs), the most numerous host cell in humans. Four cohorts, including healthy individuals and patients with sickle cell disease, were analyzed to define age-dependent changes in RBC metabolism. Over 15,700 specimens from 13,757 humans were examined, a major expansion over previous studies of RBCs in aging.

Multi-omics approaches identified chronological age-related alterations in the arginine pathway with increased arginine utilization in RBCs from older individuals. These changes were consistent across healthy and sickle cell disease cohorts and were influenced by genetic variation, sex, and body mass index. Integrating multi-omics data and metabolite quantitative trait loci (mQTL) in humans and 525 diversity outbred mice functionally linked metabolism of arginine during RBC storage to increased vesiculation - a hallmark of RBC aging - and lower post-transfusion hemoglobin increments. Thus, arginine metabolism is a biomarker of RBC and organismal aging, suggesting potential new targets for addressing sequelae of aging.

Brain aging is compared between Cercopithecinae (macaques and baboons), non-human Hominidae (chimpanzees, orangutans, and gorillas), and their close relative, humans. β-amyloid deposition in the form of senile plaques (SPs) and cerebral β-amyloid angiopathy (CAA) is a frequent neuropathological change in non-human primate brain aging. SPs are usually diffuse, whereas SPs with dystrophic neurites are rare. Tau pathology, if present, appears later, and it is generally mild or moderate, with rare exceptions in rhesus macaques and chimpanzees. Behavior and cognitive impairment are usually mild or moderate in aged non-human primates.

In contrast, human brain aging is characterized by early tau pathology manifested as neurofibrillary tangles (NFTs), composed of paired helical filaments (PHFs), progressing from the entorhinal cortex, hippocampus, temporal cortex, and limbic system to other brain regions. β-amyloid pathology appears decades later, involves the neocortex, and progresses to the paleocortex, diencephalon, brain stem, and cerebellum. SPs with dystrophic neurites containing PHFs and CAA are common.

Cognitive impairment and dementia of Alzheimer's type occur in about 1-5% of humans aged 65 and about 25% aged 85. In addition, other proteinopathies, such as limbic-predominant TDP-43 encephalopathy, amygdala-predominant Lewy body disease, and argyrophilic grain disease, primarily affecting the archicortex, paleocortex, and amygdala, are common in aged humans but non-existent in non-human primates. These observations show that human brain aging differs from brain aging in non-human primates, and humans constitute the exception among primates in terms of severity and extent of brain aging damage.

Ageing is generally regarded as a non-adaptive by-product of evolution. Based on this premise three classic evolutionary theories of ageing have been proposed. These theories have dominated the literature for several decades. Despite their individual nuances, the common thread which unites them is that they posit that ageing results from a decline in the intensity of natural selection with chronological age. Empirical evidence has been identified which supports each theory. However, a consensus remains to be fully established as to which theory best accounts for the evolution of ageing.

A consequence of this uncertainty are counter arguments which advocate for alternative theoretical frameworks, such as those which propose an adaptive origin for ageing, senescence, or death. Given this backdrop, this review has several aims. Firstly, to briefly discuss the classic evolutionary theories. Secondly, to evaluate how evolutionary forces beyond a monotonic decrease in natural selection can affect the evolution of ageing. Thirdly, to examine alternatives to the classic theories. Finally, to introduce a pluralistic interpretation of the evolution of ageing. The basis of this pluralistic theoretical framework is the recognition that certain evolutionary ideas will be more appropriate depending on the organism, its ecological context, and its life history.

Recently, cellular senescence-induced unstable carotid plaques have gained increasing attention. In this study, we utilized bioinformatics and machine learning methods to investigate the correlation between cellular senescence and the pathological mechanisms of unstable carotid plaques. Our aim was to elucidate the causes of unstable carotid plaque progression and identify new therapeutic strategies. First, differential expression analysis was performed on a test set to identify differentially expressed genes (DEGs) between the unstable plaque group and the control group. These DEGs were intersected with cellular senescence-associated genes to obtain 40 cellular senescence-associated (CSA)-DEGs.

First, we investigated the expression and function of CSA-DEGs in unstable carotid plaques. The expression of CSA-DEGs in cells from unstable carotid plaques differed significantly from the control group. These genes are mainly related to cellular senescence, apoptosis, cell proliferation regulation, and inflammatory response. Typically, the characteristics of cellular senescence are described as irreversible proliferation arrest and senescence-associated secretory phenotype (SASP). Additionally, these genes are involved in pathways such as the MAPK signaling pathway, PI3K-Akt signaling pathway, FoxO signaling pathway, and HIF-1 signaling pathway. These pathways play crucial roles in the aging process, and their dysregulation is closely associated with the progression of unstable carotid plaques. Interestingly, we also observed that CSA-DEGs are closely related to T lymphocyte proliferation and cellular immunity, which is consistent with previous studies.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder. The hallmark of RA is progressive joint disease, with potential for systemic involvement. Understanding the RA disease spectrum with recognition of at risk individuals has propelled RA research into prevention strategies. The generation of IgA class anticitrullinated protein antibodies (ACPAs) in individuals at risk of RA, combined with epidemiological links with smoking and periodontal disease, points to a mucosal origin of inflammation. The mucosal origin hypothesis proposes that localised inflammation at mucosal sites can initiate a broader immune response, via T cell activation and a subsequent inflammatory cytokine cascade, leading to B cell antibody production. Supporting this, an immunoglobulin class switch from IgA ACPAs to IgG ACPAs indicates potential triggering of systemic autoimmunity by diverse antigenic stimuli at mucosal sites. This shift, accompanied with broadening of antibody targets, suggests that mucosal barrier deterioration and the ensuing spread of an IgG ACPA response might be more significant in the initial stages of RA than the loss of tolerance to self-antigens.

Profiling of the gut microbiome in individuals at risk of RA and people diagnosed with RA consistently demonstrates a dysbiotic microbiome when compared with healthy controls. However, there remains little consensus on the bacterial constituent members of an RA-related dysbiosis. Subsequently, a variety of gut bacteria have been implicated as a potential impetus in the development of RA, none more so than Prevotella copri. Prevotella species have been demonstrated to be overabundant in new-onset rheumatoid arthritis (NORA), in at risk individuals and especially those with genetic risk. Their abundance decreases after disease-modifying antirheumatic drug (DMARD) therapy, with reversion to a eubiotic state on treatment. Furthermore, mouse models support a role for Prevotellaceae strains derived from patients with RA in RA development. However, Prevotellaceae overabundance does not appear to be an ubiquitous finding across all RA gut microbiome studies.

This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional and temporal changes in the gut microbiome in RA progressors versus non-progressors. Our data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon.

As current treatments for Alzheimer's disease (AD) lack disease-modifying interventions, novel therapies capable of restraining AD progression and maintaining better brain function have great significance. Anti-inflammatory extracellular vesicles (EVs) derived from human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) hold promise as a disease-modifying biologic for AD. This study directly addressed this issue by examining the effects of intranasal (IN) administrations of hiPSC-NSC-EVs in 3-month-old 5xFAD mice.

IN administered hiPSC-NSC-EVs incorporated into microglia, including plaque-associated microglia, and encountered astrocytes in the brain. Single-cell RNA sequencing revealed transcriptomic changes indicative of diminished activation of microglia and astrocytes. Multiple genes linked to disease-associated microglia, NLRP3-inflammasome, and IFN-1 signalling displayed reduced expression in microglia. Astrocytes also displayed reduced expression of genes linked to IFN-1 and interleukin-6 signalling. Furthermore, the modulatory effects of hiPSC-NSC-EVs on microglia in the hippocampus persisted 2 months post-EV treatment without impacting their phagocytosis function. The extent of astrocyte hypertrophy, amyloid-beta plaques, and p-tau were also reduced in the hippocampus. Such modulatory effects of hiPSC-NSC-EVs also led to better cognitive and mood function.

Thus, early hiPSC-NSC-EV intervention in AD can maintain better brain function by reducing adverse neuroinflammatory signalling cascades, amyloid-beta plaque load, and p-tau. These results reflect the first demonstration of the efficacy of hiPSC-NSC-EVs to restrain neuroinflammatory signalling cascades in an AD model by inducing transcriptomic changes in activated microglia and reactive astrocytes.