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Results for “aging hallmarks”

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PubMed2006

Genetics of aging: implications for drug discovery and development.

Aging is not a passive activity, but an actively regulated metabolic process. Specific genes have been identified that regulate aging, although aging, and consequently longevity, is only partially under genetic influence. It is also possible to increase life span by environmental modification; for example, caloric restriction can increase life span. Because human life span is long, directly studying aging in humans is impractical. Fortunately, significant insights into aging can be achieved by studying short-lived organisms, such as yeast, worms, and fruit flies. Many of the molecular pathways regulating aging in these lower organisms are conserved in mammals and overlap with pathways regulating metabolism. For example, an insulin-growth hormone signaling system has been implicated in regulating aging and longevity in both worms and mammals. Furthermore, the dysregulation of glucose homeostasis is a hallmark of aging in humans. In fact, type 2 diabetes, a disease of glucose homeostasis, can be conceptualized as a form of accelerated aging. Consistent with this, aging and diabetes are both common risk factors for a wide range of diseases. Because aging and diabetes are intimately related at a molecular level, diabetes may be able to provide the link between disease treatment (eg, diabetes) and the prevention of age-related diseases. If specific molecular pathways controlling the rate of aging can be modulated genetically, then perhaps they can be modulated pharmacologically. These insights may ultimately have an important impact on the discovery and development of drugs to both treat and prevent a wide range of diseases.

Aging↗
PubMed1991

Age-related disruption of circadian rhythms: possible relationship to memory impairment and implications for therapy with magnetic fields.

Disorganization of circadian rhythms, a hallmark of aging, may be related causally to the progressive deterioration of memory functions in senescence and possibly Alzheimer's disease (AD). In experimental animals, disruption of circadian rhythms produces retrograde amnesia by interfering with the circadian organization of memory processes. The circadian system is known to be synchronized to external 24 h periodicities of ambient light by a neural pathway extending from the retina to the suprachiasmatic nucleus (SCN) of the anterior hypothalamus. There is also evidence that the earth's magnetic field is a time cue ("Zeitgeber") of circadian organization and that shielding of the ambient magnetic field leads to disorganization of the circadian rhythms in humans. Since aging is associated with a delay of the circadian rhythm phase, and since light, which phase advances circadian rhythms, mimics the effects of magnetic fields on melatonin secretion, we postulate that application of magnetic fields might improve memory functions in the elderly as a result of resynchronization of the circadian rhythms. Moreover, since the circadian rhythm organization is more severely disrupted in patients with AD, it is possible that magnetic treatment might prove useful also in improving memory functions in these patients. If successful, application of magnetic fields might open new avenues in the management of memory disturbances in the elderly and possibly in AD.

Adult↗
PubMedDate not supplied

Physiologic aspects of aging: impact on cancer management and decision making, part I.

A gradual diminution in the physiologic reserve or functional capacity over time is the characteristic hallmark of aging, and this has a direct impact on the choice of cancer therapy and its toxicity profile in elderly patients with cancer. With the expected rapid rise of the older population as a subgroup, oncologists will increasingly treat elderly patients. Provision of competent care to this increasing pool of older patients with cancer necessitates that oncology professionals become familiar with age-associated changes in organ physiology and their impact on cancer treatment and toxicity. In this comprehensive review, we have listed changes in cardiovascular, gastrointestinal, pulmonary, and renal physiology with aging. Also enumerated is the impact of these changes on cancer therapy and toxicity in each organ system-based section. Cardiovascular changes primarily lead to reduction of the cardiac functional reserve, with a consequent increase in the risk of congestive heart failure. Changes in gastrointestinal physiology lead to increased mucosal damage. A reduction in pulmonary reserve has implications for postradiation complications, and a decline in renal function leads to an increased potential for nephrotoxicity. These changes impair the ability of older patients with cancer to tolerate cancer therapy and increase their risk of toxicities. This may lead to an overall decline in functional status, resulting frailty, poor quality of life, and ultimately poor outcomes. Becoming familiar with age-related physiologic changes is the first step for oncologists seeking to better tailor their treatments. This, combined with adoption of some of the clinical interventions suggested in this review, can help better manage the geriatric oncology patient. Further research is necessary for the development of more specific evidence-based recommendations.

Aged↗
PubMed2026

Macrophage regulation of extracellular matrix remodeling in aging skeletal muscle.

The extracellular matrix (ECM) is a dynamic structural network that supports tissue architecture and regulates cell function. It is primarily composed of collagens, elastin, proteoglycans, and glycoproteins, which are synthesized by canonical and non-canonical ECM-producing cells. During aging, the ECM undergoes progressive changes in structure and composition, a process recently recognized as the 13th hallmark of aging. In skeletal muscle (SKM), age-associated ECM remodeling, largely regulated by immune system-ECM crosstalk, contributes to sarcopenia and impaired regeneration. Macrophages (MΦs), as key innate immune cells, regulate ECM dynamics both indirectly by activating canonical ECM-producing cells and directly by synthesizing ECM components. Notably, a distinct subset of ECM-producing MΦs that express collagen (COL+ MΦs) has been identified across multiple tissues, although their function in SKM homeostasis and aging remains poorly understood. Here, we review current knowledge of ECM production and remodeling, with special emphasis on MΦ involvement, including COL+ MΦs, as critical regulators of fibrogenesis, especially during SKM aging and regeneration.

Extracellular Matrix↗
PubMed2025

Aging and Corneal Nerve Health: Mechanisms of Degeneration and Emerging Therapies for the Cornea.

Corneal nerves play a crucial role in maintaining ocular surface homeostasis by supporting the functional integrity of corneal epithelial, stromal, and endothelial cells; modulating tear secretion; and facilitating sensory responses essential for overall ocular health. With advancing age, these highly specialized peripheral sensory fibers undergo progressive attrition and morphologic distortion driven by the canonical hallmarks of aging including genomic instability, impaired proteostasis, mitochondrial dysfunction, and chronic low-grade inflammation. The resulting neuro-immune dysregulation reduces trophic support, delays wound healing, and predisposes older adults to dry-eye disease, neurotrophic keratopathy, and postsurgical hypoesthesia. Age-exacerbating cofactors including diabetes, dyslipidemia, neurodegenerative disorders, topical preservatives, chronic contact-lens wear, herpes zoster ophthalmicus, and ocular-surface hypoxia further accelerate sub-basal nerve rarefaction and functional decline. This review provides an overview of age-related physiological alterations in ocular surface nerves, with a particular emphasis on corneal innervation. It also discusses risk factors that speed up these changes. Given the inherently limited regenerative capacity of corneal nerves and their inability to fully restore to baseline conditions following injury or degeneration, it is critical to identify and develop effective strategies aimed at mitigating or delaying physiological nerve degeneration and promoting nerve regeneration. This review also brings up emerging therapeutic strategies, including regenerative medicine, neuroprotective agents, and lifestyle interventions aimed at mitigating age-related corneal nerve degeneration.

Humans↗
PubMed2025

Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.

The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Animals↗
PubMed2025

Telomeric DNA damage response mediates neurotoxicity of Aβ42 oligomers in Alzheimer's disease.

Ageing is the major risk factor for Alzheimer's disease (AD), the most common neurodegenerative disorder. DNA damage is a hallmark of ageing, particularly when occurring at telomeres, genomic regions vulnerable to oxidative damage and often challenging for the cell to repair. Here, we show that brains of 3xTg-AD mice, an established AD model characterized by amyloid-β (Aβ)-induced pathology, exhibit increased activation of DNA damage response (DDR) pathways at telomeres. Exposure of mouse primary hippocampal neurons to 42-residue Aβ (Aβ42) oligomers, a significant pathogenetic contributor to AD, triggers telomeric DDR by increasing the levels of reactive oxygen species caused by calcium imbalance. Antisense oligonucleotides targeting non-coding RNAs generated at damaged telomeres in vivo (in 3xTg-AD mice) and in vitro reduce neurotoxicity in iPSC-derived human cortical neurons and mouse primary neurons while inhibiting Aβ42-induced telomeric DDR, and restore transcriptional pathways altered by Aβ and found dysregulated in AD patients. These results unveil an unexpected role of telomeric DNA damage responses in Alzheimer's disease pathogenesis, and suggest a novel target for the development of RNA-based therapies.

Alzheimer Disease↗
PubMed2004

Heme, iron, and the mitochondrial decay of ageing.

Heme, the major functional form of iron, is synthesized in the mitochondria. Although disturbed heme metabolism causes mitochondrial decay, oxidative stress, and iron accumulation, all of which are hallmarks of ageing, heme has been little studied in nutritional deficiency, in ageing, or age-related disorders such as Alzheimer's disease (AD). Biosynthesis of heme requires Vitamin B(6), riboflavin, biotin, pantothenic acid, and lipoic acid and the minerals zinc, iron, and copper, micronutrients are essential for the production of succinyl-CoA, the precursor for porphyrins, by the TCA (Krebs) cycle. Only a small fraction of the porphyrins synthesized from succinyl-CoA are converted to heme, the rest are excreted out of the body together with the degradation products of heme (e.g. bilirubin). Therefore, the heme biosynthetic pathway causes a net loss of succinyl-CoA from the TCA cycle. The mitochondrial pool of succinyl-CoA may limit heme biosynthesis in deficiencies for micronutrients (e.g. iron or biotin deficiency). Ageing and AD are also associated with hypometabolism, increase in heme oxygenase-1, loss of complex IV, and iron accumulation. Heme is a common denominator for all these changes, suggesting that heme metabolism maybe altered in age-related disorders. Heme can also be a prooxidant: it converts less reactive oxidants to highly reactive free radicals. Free heme has high affinity for different cell structures (protein, membranes, and DNA), triggering site-directed oxidative damage. This review discusses heme metabolism as related to metabolic changes seen in ageing and age-related disorders and highlights the possible role in iron deficiency.

Aconitate Hydratase↗
PubMed2026

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs)-arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin)-led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Actin dysfunction also displayed a more "aged" transcriptome using previously validated transcriptomics clocks, and broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting some links between aging and actin across organisms. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how changes in actin integrity correlate with diverse aging phenotypes across tissues. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics can potentially influence aging.

actin↗
PubMed2026

The interplay of epigenetic remodelling and transposon-mediated genomic instability in ageing and longevity.

Ageing and age-related diseases are the result of complex biological processes that progressively cause deterioration of cellular and tissue function. Among the key hallmarks of ageing are epigenetic alterations and genomic instability, both of which are closely interconnected and significantly contribute to the ageing process. The epigenome, encompassing both DNA and histone modifications, regulates gene expression and maintains genomic integrity throughout life. With age, these regulatory systems become dysregulated, leading to genome-wide changes in chromatin structure, histone modifications and the reactivation of transposable elements (TEs). TEs, typically silenced in heterochromatic regions, become active in aged cells, contributing to genomic instability, mutagenesis, inflammation and metabolic disruption. Despite their significant implications, the role of TEs in the ageing process remains underexplored, and the interplay between epigenomic remodelling and TE activity remains poorly understood. In this review, we explore the molecular mechanisms underlying epigenetic alterations and TE reactivation during ageing, the impact of these changes on genomic stability and the potential therapeutic interventions targeting this interplay. By deciphering the role of epigenetic modifications and TE derepression in the ageing process, we aim to highlight novel avenues for anti-ageing and pro-longevity strategies.

Aging↗
PubMed2004

Aging in the rat hippocampus is associated with widespread reductions in the number of glutamate decarboxylase-67 positive interneurons but not interneuron degeneration.

Increased excitability of principal excitatory neurons is one of the hallmarks of aging in the hippocampus, signifying a diminution in the number and/or function of inhibitory interneurons with aging. To elucidate this, we performed comprehensive GABA-ergic interneuron cell counts in all layers of the dentate gyrus and the CA1 and CA3 subfields, using serial sections from adult, middle-aged and aged Fischer 344 rats. Sections were immunostained for glutamate decarboxylase-67 (GAD-67, a synthesizing enzyme of GABA) and GAD-67 immunopositive interneurons were counted using an unbiased cell counting method, the optical fractionator. Substantial declines in the absolute number of GAD-67 immunopositive interneurons were found in all hippocampal layers/subfields of middle-aged and aged animals, in comparison with the adult animals. However, the counts were comparable between the middle-aged and aged groups for all regions. Interestingly, determination of the absolute number of interneurons using neuron-specific nuclear antigen (NeuN) expression in the strata oriens and radiatum of CA1 and CA3 subfields revealed an analogous number of interneurons across the three age groups. Furthermore, the ratio of GAD-67 immunopositive and NeuN positive interneurons decreased from adult age to middle age but remained relatively static between middle age and old age. Collectively, the results underscore that aging in the hippocampus is associated with wide-ranging decreases in the number of GAD-67 immunopositive interneurons and most of the age-related changes in GAD-67 immunopositive interneuron numbers transpire by middle age. Additionally, this study provides novel evidence that age-related reductions in hippocampal GAD-67 immunopositive interneuron numbers are due to loss of GAD-67 expression in interneurons rather than interneuron degeneration.

Age Factors↗
PubMed2002

Effects of cholinergic lesions produced by infusions of 192 IgG-saporin on glucocorticoid receptor mRNA expression in hippocampus and medial prefrontal cortex of the rat.

Principal neurons in the hippocampus and prefrontal cortex of the rat have been identified as targets for glucocorticoids involved in the hypothalamic-pituitary-adrenocortical stress response. Alterations in mRNA expression for glucocorticoid receptors in each of these regions have been shown to affect the negative feedback response to corticosterone following an acute stressor. Both decreases in forebrain glucocorticoid receptors and in the efficiency of adrenocortical feedback have been observed in normal aging, and have been selectively induced with experimental lesions or manipulations in neurotransmitter systems. The current study investigated the possibility that a loss of cholinergic support from cells in the basal forebrain, a hallmark of aging, contributes to the selective age-related loss of glucocorticoid receptor mRNA expression at cholinoceptive target sites that include the hippocampus and medial prefrontal cortex. Lesions of the basal forebrain cholinergic system in young adult rats were made by microinjections of the immunotoxin 192 IgG-saporin into the medial septum/vertical limb of the diagonal band and substantia innominata/nucleus basalis. Basal levels of circulating glucocorticoids were unaffected by the lesions. Analysis of both mineralocorticoid and glucocorticoid receptor mRNA expression revealed a significant decrease in glucocorticoid receptor mRNA in the hippocampus and medial prefrontal cortex, with spared expression at subcortical sites and no detectable change in mineralocorticoid receptor mRNA in any of the examined regions. Thus, rats with lesions of the basal forebrain cholinergic system recapitulate some of the detrimental effects of aging associated with glucocorticoid-mediated stress pathways in the brain.

Acetylcholine↗
PubMed2005

Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation.

Cellular senescence suppresses cancer by arresting cells at risk of malignant tumorigenesis. However, senescent cells also secrete molecules that can stimulate premalignant cells to proliferate and form tumors, suggesting the senescence response is antagonistically pleiotropic. We show that premalignant mammary epithelial cells exposed to senescent human fibroblasts in mice irreversibly lose differentiated properties, become invasive and undergo full malignant transformation. Moreover, using cultured mouse or human fibroblasts and non-malignant breast epithelial cells, we show that senescent fibroblasts disrupt epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. Furthermore, we identify MMP-3 as the major factor responsible for the effects of senescent fibroblasts on branching morphogenesis. Our findings support the idea that senescent cells contribute to age-related pathology, including cancer, and describe a new property of senescent fibroblasts - the ability to alter epithelial differentiation - that might also explain the loss of tissue function and organization that is a hallmark of aging.

Animals↗
PubMed2004

'Accelerated aging': a primrose path to insight?

Organism envy afflicts most researchers who work on aging in mice; how frustrating it is to see the worm and fly biologists nail down milestone after milestone, citation after citation! Surely genetic trickery can produce mice that age in a comparable jiffy? Alas, our near-total ignorance of what times the aging process makes it hard to guess what genes to tweak, if indeed aging can be mimicked a presto. Building a case that a given short-lived mutant ages quickly is a steep and thorny path, requiring more than just plucking a symptom here and there from a list of things that sometimes go wrong in old people or old mice. The hallmark of aging is that a lot goes wrong more or less at the same time, in 2-year-old mice, 10-year-old dogs and 70-year-old people. Finding ways to damage one or two systems in a 6-week or 6-month-old mouse is not too hard to do, but the implications of such studies for improved understanding of aging per se are at best indirect and at worst imaginary and distracting.

Aged↗
PubMed1984

Biological and clinical consequences of longitudinal studies in rodents: their possibilities and limitations. An overview.

Rats and mice are used in gerontological research primarily because of their relatively short life spans, ease of handling, and the relatively low costs of production and maintenance under controlled environmental conditions of large number of rodents as compared to larger laboratory animal species. They are being used as models for studying intrinsic aging processes, processes that give rise to diseases associated with aging, and the influence of environmental factors on these processes. Contrary to the situation in man, longitudinal studies in rodents can be conducted under well controlled environmental conditions. It has been shown that multiple pathology, the hallmark of aging in man, also occurs in inbred strains of rodents. Some of these lesions are genetically determined and some of them are randomly distributed amongst members of the same inbred strain. Serial killing experiments are necessary to obtain information on the time of development of these lesions in order to interpret properly the outcome of investigations. Furthermore, it has been shown that a considerable variation can exist in the observed maximum ages of the longest-lived animals in cohorts of rats kept under well controlled conditions. For this reason, caution should be exercised in interpreting data from studies which claim maximum lifespan prolongation.

Aging↗
PubMed1988

Aging and vascular responsiveness.

With aging, the blood vessel wall becomes hyperreactive--presumably because of an augmented vasoconstrictor and a reduced vasodilator responsiveness. Autonomic nerves, vascular smooth muscle, and endothelial cells may contribute to these changes. It seems unlikely that augmented vasoconstriction following alpha-adrenergic activation plays a major role in the increased peripheral resistance seen in the elderly human. There are no major age-related changes in the responsiveness of vascular smooth muscle to angiotensin II, histamine, or potassium chloride. By contrast, the vasoconstrictor effects of 5-hydroxytryptamine (serotonin) are augmented, and the tachyphylaxis to the monoamine is reduced with aging. There are no indications of a major abnormality in either responses to vasodilator nerves or endothelium-dependent vasodilators. However, the beta-adrenergic responsiveness of most arteries is reduced, whereas that of the veins is not affected by age. When it is exposed to agents acting directly, arterial smooth muscle's ability to relax is not altered with senescence. Thus, the augmented responsiveness to the vasoconstrictor effects of serotonin and the reduced response to the beta-adrenergic dilator effects of catecholamines appear to be the hallmark of aging in the precapillary vessels.

Aged↗
PubMed2001

Ageing and the immune system.

Immune system alterations during ageing are complex and pleiotropic, suggestive of remodelling or altered regulation, rather than simple immune deficiency. The most dramatic changes with age occur within the T cell compartment, the arm of the immune system that protects against pathogens and tumours, consistent with the increased incidence and severity of infection and cancer in the elderly. Indeed, autopsy studies confirm infection as the major cause of death in the very old. Increased serum levels of inflammatory mediators are another hallmark of ageing, suggestive of either regulatory defects or an ongoing attack on sub-clinical neoplastic disease or infection. Qualitative changes in antibody production, including those secreted by the gut mucosal immune compartment, affect responses to foreign antigens as well as to prophylactic vaccines. Innate immunity, the first line of defence that precedes the antigen-specific T and B cell responses, also undergoes changes with age. Some of the immune effects associated with ageing are secondary to overall organismic changes, such as alterations in the viscosity of cell membranes and proteolytic cellular machinery. Evidence suggesting that immune system changes may be involved in some major age-related pathologies, such as atherosclerosis and Alzheimer's disease, will be discussed.

Aging↗
PubMedDate not supplied

Oxidative stress and brain aging: is zinc the link?

Zn(2+) dyshomeostasis has been strongly linked to neuronal injury in many neurological conditions. Toxic accumulation of intracellular free Zn(2+) ([Zn(2+)](i)) may result from either flux of the cation through glutamate receptor-associated channels, voltage-sensitive calcium channels, or Zn(2+)-sensitive membrane transporters. Injurious [Zn(2+)](i) rises can also result from release of the cation from intracellular sites such as metallothioneins (MTs) and mitochondria. Chronic inflammation and oxidative stress are hallmarks of aging. Zn(2+) homeostasis is affected by oxidative stress, which is a potent trigger for detrimental Zn(2+) release from MTs. Interestingly, Zn(2+) itself is a strong inducer of oxidative stress by promoting mitochondrial and extra-mitochondrial production of reactive oxygen species. In this review, we examine how Zn(2+) dyshomeostasis and oxidative stress might act synergistically to promote aging-related neurodegeneration.

Aging↗