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Werner syndrome is the hallmark premature aging disease, where the patients appear much older than their chronological age. The Werner protein, defective in this disorder, is a DNA helicase and an exonuclease, and it participates in pathways of DNA repair, recombination, transcription and replication. The function and role of this protein is discussed in the light of how it functions in the aging process.
Loss of lean body mass (LBM) is a hallmark of aging and of acute and chronic illness. Loss of more than 40% of lean mass is not compatible with life. The causes of loss of LBM in aging remain obscure, although changes in growth hormone production, physical activity and the cytokines interleukin-1 beta and tumor necrosis factor-alpha may play a role. The usefulness of a disease model based on rheumatoid arthritis (RA) is considered, in which all these changes occur to a greater degree and independently of age. RA is a common autoimmune condition in which cytokine production is increased, LBM is reduced and mortality is greatly accelerated. These observations suggest that, with respect to body composition at least, RA represents a model of "accelerated" aging. A hypothesis is presented that unifies metabolic and immunologic observations and changes in body composition. The interrelationship of the immune system and body composition is an important area that deserves further investigation.
Progeroid syndromes (PSs) constitute a group of disorders characterized by clinical features mimicking physiological aging at an early age. In some of these syndromes, biological hallmarks of aging are also present, whereas in others, a link with physiological aging, if any, remains to be elucidated. These syndromes are clinically and genetically heterogeneous and most of them, including Werner syndrome and Hutchinson-Gilford progeria, are known as 'segmental aging syndromes', as they do not feature all aspects usually associated to physiological aging. However, all the characterized PSs enter in the field of rare monogenic disorders and several causative genes have been identified. These can be separated in subcategories corresponding to (i) genes encoding DNA repair factors, in particular, DNA helicases, and (ii) genes affecting the structure or post-translational maturation of lamin A, a major nuclear component. In addition, several animal models featuring premature aging have abnormal mitochondrial function or signal transduction between membrane receptors, nuclear regulatory proteins and mitochondria: no human pathological counterpart of these alterations has been found to date. In recent years, identification of mutations and their functional characterization have helped to unravel the cellular processes associated to segmental PSs. Recently, several studies allowed to establish a functional link between DNA repair and A-type lamins-associated syndromes, evidencing a relation between these syndromes, physiological aging and cancer. Here, we review recent data on molecular and cellular bases of PSs and discuss the mechanisms involved, with a special emphasis on lamin A-associated progeria and related disorders, for which therapeutic approaches have started to be developed.
Reactivation and dysregulation of the mTOR signaling pathway are a hallmark of aging and chronic lung disease; however, the impact on microvascular progenitor cells (MVPCs), capillary angiostasis, and tissue homeostasis is unknown. While the existence of an adult lung vascular progenitor has long been hypothesized, these studies show that Abcg2 enriches for a population of angiogenic tissue-resident MVPCs present in both adult mouse and human lungs using functional, lineage, and transcriptomic analyses. These studies link human and mouse MVPC-specific mTORC1 activation to decreased stemness, angiogenic potential, and disruption of p53 and Wnt pathways, with consequent loss of alveolar-capillary structure and function. Following mTOR activation, these MVPCs adapt a unique transcriptome signature and emerge as a venous subpopulation in the angiodiverse microvascular endothelial subclusters. Thus, our findings support a significant role for mTOR in the maintenance of MVPC function and microvascular niche homeostasis as well as a cell-based mechanism driving loss of tissue structure underlying lung aging and the development of emphysema.
Age-related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age-related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1-XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1-/Δ mice, which models a human progeroid syndrome, were compared to age-matched wild-type (WT) and old WT mice. By 3-months-of age, Ercc1-/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1-/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ-H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1-/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age-related retinal degeneration.
Telomeres are repetitive DNA sequences at the ends of linear chromosomes. Telomerase, a cellular reverse transcriptase, helps maintain telomere length in human stem cells, reproductive cells and cancer cells by adding TTAGGG repeats onto the telomeres. However, most normal human cells do not express telomerase and thus each time a cell divides some telomeric sequences are lost. When telomeres in a subset of cells become short (unprotected), cells enter an irreversible growth arrest state called replicative senescence. Cells in senescence produce a different constellation of proteins compared to normal quiescent cells. This may lead to a change in the homeostatic environment in a tissue-specific manner. In most instances cells become senescent before they can become cancerous; thus, the initial growth arrest induced by short telomeres may be thought of as a potent anti-cancer protection mechanism. When cells can be adequately cultured until they reach telomere-based replicative senescence, introduction of the telomerase catalytic protein component (hTERT) into telomerase-silent cells is sufficient to restore telomerase activity and extend cellular lifespan. Cells with introduced telomerase are not cancer cells, since they have not accumulated the other changes needed to become cancerous. This indicates that telomerase-induced telomere length manipulations may have utility for tissue engineering and for dissecting the molecular mechanisms underlying genetic diseases, including cancer.
During aging, the brain parenchyma of animals and humans share many similarities, both in the gray and the white matter. Unfortunately, until now, neither aged animals nor animal models reproduce the two hallmarks of aging of the human brain: senile plaques and tangles. Therefore, observations performed on animals are limited to some aspects of the involutive process which affects brain parenchyma during aging and their appropriateness to the human situation. One striking aspect concerns the occurrence of vacuolated necrotic cells whose number increases with advancing age. These cells can constitute markers of the brain involutive process and they characterize, both in animal and human, the more vulnerable areas of the brain affected by the neuronal rarefaction. Experimental animal models can be used to study the various conditions which sustain the cell survival and to determine, at the cellular level, the factors leading the brain parenchyma to an irreversible state of degradation.
IGF-1 is a potent growth factor for both motor neurones and skeletal muscle. Muscle IGF-1 is known to provide target-derived trophic effects on motor neurones. Therefore, IGF-1 overexpression in muscle is effective in delaying or preventing deleterious effects of ageing in both tissues. Since age-related decline in muscle function stems partly from motor neurone loss, a tetanus toxin fragment-C (TTC) fusion protein was created to target IGF-1 to motor neurones. IGF-1-TTC retains IGF-1 activity as indicated by [(3)H]thymidine incorporation into L6 myoblasts. Spinal cord motor neurones effectively bound and internalized the IGF-1-TTC in vitro. Similarly, IGF-1-TTC injected into skeletal muscles was taken up and retrogradely transported to the spinal cord in vivo, a process prevented by denervation of injected muscles. Three monthly IGF-1-TTC injections into muscles of ageing mice did not increase muscle weight or muscle fibre size, but significantly increased single fibre specific force over aged controls injected with saline, IGF-1, or TTC. None of the injections changed muscle fibre type composition, but neuromuscular junction post-terminals were larger and more complex in muscle fibres injected with IGF-1-TTC, compared to the other groups, suggesting preservation of muscle fibre innervation. This work demonstrates that induced overexpression of IGF-1 in spinal cord motor neurones of ageing mice prevents muscle fibre specific force decline, a hallmark of ageing skeletal muscle.
Accumulation of CD28(null)CD8(+) T cells is considered as one of the hallmarks of aging in the human immune system. However, the precise changes of CD28(null)CD8(+) T cells, compared to those of the precursor CD28(+)CD8(+) memory T cells, have not been determined. In this study, we present an analysis of the global gene expression profiles of CD28(+) and CD28(null) memory phenotype CD8(+) T cells. These two CD8(+) T subsets exhibited an overall similar gene expression profile with only a few dozen genes that were differentially expressed. A wide range of functions, including co-stimulation, effector activity, signaling, and transcription, were possessed by these differentially expressed genes, reflecting significant functional changes of CD28(null) memory phenotype CD8(+) T cells from their CD28(+) counterparts. In addition, CD28(null) memory CD8(+) T cells expressed several natural killer cell receptors and high levels of granzymes, perforin, and FasL, indicating an increasing capacity for cytotoxicity during memory CD8(+) T-cell aging. Interestingly, in vitro culture of these two subsets with interleukin-15 showed that similar gene expression changes occurred in both subsets. Our analysis provides the gene expression portraits of CD28(null) memory phenotype CD8(+) T cells and alteration from their CD28(+) counterparts and suggests potential mechanisms of T-cell aging.
OBJECTIVE: Reduced arterial elasticity is a hallmark of aging in healthy humans independently of diseases and endothelial-cell injury and dysfunction may be responsible for this fall in arterial elasticity. We hypothesized that circulating endothelial progenitor cells (EPCs) are involved in endothelial repair and that lack of EPCs contributes to impaired arterial elasticity. METHODS: A total of 56 healthy male volunteers were divided into young (n = 26) and elderly (n = 30) groups. Large and small artery elasticity indices were non-invasively assessed by using pulse wave analysis. Flow cytometer was used to count the number of circulating CD34(+) mononuclear cells (MNCs), which were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. EPCs were characterized as adherent cells double positive staining for DiI-acLDL uptake and lectin binding with using fluorescent microscope. RESULTS: C(1) (large artery elasticity index) and C(2) (small artery elasticity index) were significantly reduced in the elderly group compared with those in the young group (11.73 +/- 1.45 vs 16.89 +/- 1.69 ml/mm Hg x 10, P < 0.001; 8.40 +/- 1.45 vs 10.58 +/- 1.18 ml/mm Hg x 100, P < 0.001 respectively). In parallel, the number of circulating EPCs was significantly reduced in the elderly group compared with the young group (0.13 +/- 0.02 vs 0.17 +/- 0.04%, P < 0.05). The number of circulating EPCs correlated with C(1) large and C(2) small artery elasticity indices (r = 0.47, P < 0.01; r = 0.4, P < 0.01). Fluorescent microscope was used to identify EPCs, which were double positive staining for DiI-acLDL uptake and lectin binding. CONCLUSION: The present findings suggested that the fall in circulating EPCs with subsequently impaired endothelial-cell repair and function might contribute to reduced arterial elasticity in humans with aging. The decrease in circulating EPCs could serve as a surrogate biologic measure of vascular function and human age.
Various mechanisms have been argued for skin wrinkling, one of the hallmarks of aging. We hypothesize that chronic sympathetic bias is a previously unrecognized mechanism for wrinkling. In the acute setting of water immersion, reversible skin wrinkling is a well-known reflex mediated by the autonomic nervous system. We postulate that skin wrinkling results as a local maladaptive manifestation of a global chronic sympathetic bias that emerges during aging. The persistence of such changes may induce additional compensatory remodeling to cause permanent alteration of the skin. Sympatholytic agents may prove beneficial for arresting or ameliorating the development of wrinkles. Conditions that amplify sympathetic bias such as stress, smoking, amphetamine abuse, HIV, heart failure, and transplantation may accelerate wrinkling. Other common diseases of the skin may also arise as particular manifestations of aberrant autonomic activity through induction of vascular and immune dysfunctions. The temporal and spatial distribution of these dermatologic conditions may reflect variation of autonomic balance, which also regulates T helper immune balance. For all of these dermatologic conditions, local and systemic administration of drugs and medical devices that pharmacologically or electrically modulate autonomic nervous system activity may yield benefits as well.
The accumulation of lipofuscin within postmitotic cells is a recognized hallmark of aging occurring with a rate inversely related to longevity. Lipofuscin is an intralysosomal, polymeric substance, primarily composed of cross-linked protein residues, formed due to iron-catalyzed oxidative processes. Because it is undegradable and cannot be removed via exocytosis, lipofuscin accumulation in postmitotic cells is inevitable, whereas proliferative cells efficiently dilute it during division. The rate of lipofuscin formation can be experimentally manipulated. In cell culture models, oxidative stress (e.g., exposure to 40% ambient oxygen or low molecular weight iron) promotes lipofuscin accumulation, whereas growth at 8% oxygen and treatment with antioxidants or iron-chelators diminish it. Lipofuscin is a fluorochrome and may sensitize lysosomes to visible light, a process potentially important for the pathogenesis of age-related macular degeneration. Lipofuscin-associated iron sensitizes lysosomes to oxidative stress, jeopardizing lysosomal stability and causing apoptosis due to release of lysosomal contents. Lipofuscin accumulation may also diminish autophagocytotic capacity by acting as a sink for newly produced lysosomal enzymes and, therefore, interfere with recycling of cellular components. Lipofuscin, thus, may be much more directly related to cellular degeneration at old age than was hitherto believed.
The decline of tissue regenerative potential is a hallmark of ageing and may be due to age-related changes in tissue-specific stem cells. A decline in skeletal muscle stem cell (satellite cell) activity due to a loss of Notch signalling results in impaired regeneration of aged muscle. The decline in hepatic progenitor cell proliferation owing to the formation of a complex involving cEBP-alpha and the chromatin remodelling factor brahma (Brm) inhibits the regenerative capacity of aged liver. To examine the influence of systemic factors on aged progenitor cells from these tissues, we established parabiotic pairings (that is, a shared circulatory system) between young and old mice (heterochronic parabioses), exposing old mice to factors present in young serum. Notably, heterochronic parabiosis restored the activation of Notch signalling as well as the proliferation and regenerative capacity of aged satellite cells. The exposure of satellite cells from old mice to young serum enhanced the expression of the Notch ligand (Delta), increased Notch activation, and enhanced proliferation in vitro. Furthermore, heterochronic parabiosis increased aged hepatocyte proliferation and restored the cEBP-alpha complex to levels seen in young animals. These results suggest that the age-related decline of progenitor cell activity can be modulated by systemic factors that change with age.
ALTHOUGH PEOPLE AGE at different rates, changes to the composition of the human body are a hallmark of aging. As a result of such changes, disease can present differently in a person over 65 years old than it would in a younger adult or child. THIS ARTICLE IDENTIFIES the critical indicators of underlying conditions, including changes in mental status, loss of function, decrease in appetite, dehydration, falls, pain, dizziness, and incontinence. It also describes the presentation of diseases common to older adults, including depression, infection, cardiac disease, gastrointestinal disorders, thyroid disease, and type 2 diabetes.
Although people age at different rates, changes to the composition of the human body are a hallmark of aging. As a result of such changes, disease can present differently in a person over 65 years old than it would in a younger adult or child. This article identifies the critical indicators of underlying conditions, including changes in mental status, loss of function, decrease in appetite, dehydration, falls, pain, dizziness, and incontinence. It also describes the presentation of diseases common to older adults, including depression, infection, cardiac disease, gastrointestinal disorders, thyroid disease, and type 2 diabetes.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder whose clinical manifestations appear in old age. The hallmark pathological features of AD (amyloid plaques and associated proteins) are present in normal aging indivduals, suggesting that AD may result from the acceleration of normal age-related processes in the brain. The sporadic nature of most AD cases strongly argues for an environmental link that may drive AD pathogenesis; however, it is unclear when this environmental stress may occur. Therefore it is important to identify an environmental trigger(s) and to pinpoint the period during which such factors pose the greatest risk. Recently, we reported that developmental exposure of rats to the xenobiotic metal lead (Pb) resulted in a delayed overexpression (20 months later) of the amyloid precursor protein (APP) and its amyloidogenic Abeta product. Similarly, aged monkeys exposed to Pb as infants also responded in the same way. These data suggest that environmental influences occurring during brain development predetermine the expression and regulation of APP later in life, potentially influencing the course of amyloidogenesis, and argue for both an environmental trigger and a developmental origin of AD. In this review, we present evidence for the developmental basis of neurodegeneration and discuss mechanisms that may explain how perturbations during development can have long-term or delayed consequences in the aging brain.
Profound alterations in humoral and cellular immune responses are a hallmark of aging, and understanding the immunobiology of aging is key to the success of preventive vaccination strategies. With aging, while recall or memory responses to influenza viral antigens for the most part remained unaltered, primary immune responses are severely impaired. The impaired primary responses are partly due to a lack of costimulation, as providing costimulation at the time of induction of primary immune responses against influenza virus vaccine partially reversed aged-related immune dysfunction and conferred enhanced protection. Inclusion of immunomodulators that up-regulate the expression of costimulatory molecules must be considered to improve the efficacy of vaccination in the elderly, particularly to novel immunogens.
Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, is a major hallmark of aging. Post-translational modifications (PTMs) play essential roles in regulating protein activity and cellular homeostasis; however, how multiple PTMs are remodeled during skeletal muscle aging remains incompletely characterized. Here, we performed comprehensive multi-layered proteomic profiling of skeletal muscle from young (3-month-old) and aged (24-month-old) mice, systematically quantifying the global proteome together with five major PTMs: acetylation, phosphorylation, N-glycosylation, O-glycosylation, and ubiquitination. In total, we identified 5 337 proteins and mapped thousands of PTM sites, generating an integrated atlas of age-associated proteomic and PTM remodeling in skeletal muscle. Pathway enrichment analyses revealed distinct modification-specific patterns: acetylation and phosphorylation were predominantly associated with metabolic and mitochondrial-related pathways; N-glycosylation was enriched in immune- and secretory pathway-related processes; O-glycosylation was associated with muscle contraction-related pathways; and ubiquitination was preferentially linked to cytoskeletal organization in muscle cells. Correlation analyses further uncovered diverse association patterns among different PTMs across protein- and modification-level datasets. Phosphorylation and ubiquitination exhibited consistent positive associations, whereas acetylation and ubiquitination showed both inverse and concordant co-variation patterns across subsets of proteins. Phosphorylation and O-glycosylation displayed heterogeneous association patterns across different proteins, and acetylation and phosphorylation demonstrated positive correlations with distinct age-associated directional changes across protein subsets. Together, these results provide a comprehensive, multi-dimensional view of age-associated remodeling of the skeletal muscle proteome and multiple PTM layers, offering a valuable resource for understanding molecular alterations accompanying muscle aging and sarcopenia.