Skin Aging

Skin aging is one of the most studied aspects of aging because it is visible and can affect a person’s appearance, which can have significant social and psychological effects. Aging of the skin can lead to changes in skin texture, color, and elasticity, which can affect how people look and feel about themselves. Furthermore, the skin plays an important role in protecting the body from environmental factors, such as UV radiation and pollution. It also prevents excessive water loss and the entry of toxic substances and pathogens into the environment. Upon aging, the skin’s ability to perform these functions can decrease, which can have negative effects on overall health.

As the largest organ of the body exposed to the external environment, the skin endures both intrinsic and extrinsic aging factors with extrinsic aging prompted by environmental impacts and overlaying the effects of temporal aging. Intrinsic aging is a physiological process that results in several phenotypes such as, but not limited to, wrinkling, pigmentation, telangiectasis, and gradual dermal atrophy,^[1]^[2]^[3]^[4]^[5]^[6]^[7] while extrinsic aging is provoked by exterior environment and behavioral factors such as air pollution, tobacco smoking, inadequate nutrition, and sun exposure, causing wrinkles, elasticity loss, as well as rough-textured appearance.^[1]^[2] Particularly, long-term exposure to solar UV radiation is the prime factor of extrinsic skin aging referred to as photoaging.^[2]

Skin aging is accompanied by phenotypic changes in cutaneous cells along with structural and functional alterations in extracellular matrix components such collagen, elastin and proteoglycans, which are required to afford tensile strength, elasticity, and moisture to the skin.^[8]^[9] This can result in the appearance of fine lines and wrinkles, sagging skin, and a loss of facial volume. In addition, skin aging is characterized by a decrease in the level of production of hyaluronic acid, a substance that helps to maintain skin hydration and suppleness. Other intrinsic factors that contribute to skin aging include genetic inheritance, slower cell turnover, and hormonal changes, including estrogen, progesterone, and testosterone decrease, which can affect the skin structure. which can lead to a loss of skin elasticity and changes in skin cell metabolism. Additionally, changes in skin microbiota, the collection of microorganisms that live on our skin, can contribute to skin aging and the development of aging-associated skin diseases.^[8]

Extrinsic factors that can contribute to skin aging include exposure to ultraviolet (UV) radiation, cigarette smoke, pollution, and a poor diet. UV radiation from the sun is a major contributor to skin aging, causing damage to the skin cells and breaking down collagen and elastin fibers. This can result in the development of age spots, a rough texture, and uneven skin tone. Additionally, exposure to cigarette smoke and pollution can cause oxidative stress, leading to inflammation and damage to skin cells. A diet that is high in sugar, processed foods, and unhealthy fats can lead to inflammation, which can also accelerate the aging process.^[10]^[11]

Macrophages are the most abundant immune cell type in the skin and are vital for skin homeostasis and host defense.^[12] However, they have also been associated with chronic inflammation upon aging. It has been suggested that age-modified skin macrophages may promote adaptive immunity exacerbation and exhaustion, facilitating the development of proinflammatory pathologies, including skin cancer.^[12]

While the intrinsic and extrinsic aging factors are both related to phenotypic changes in dermal cells, the most significant structural changes take place in the extracellular matrix (ECM) of dermis, in which collagens, elastin, and proteoglycans impart tensile strength and hydration. The utmost longevity of these biomolecules, relative to the intracellular proteins, exposes them to accumulated damage, which in turn affects their capability to provide mechanical properties and to manage tissue homeostasis.^[13]^[14]^[15]^[16]^[17] Thus, at variance with the intracellular proteins, the half-lives of which are measured in hours or at most days,^[15] many ECM proteins exhibit half-lives measured in years. For instance, human skin and cartilage collagens types I and II have half-lives of about 15 and 95 years,^[18] while the half-lives of elastin fibers is equal to^[13] or many times longer than average human life.^[19]^[20] Therefore, in humans, ECM proteins are required to function for long years, during which time they are at risk of accumulating damage via glycation,^[21] calcium and lipid accumulation,^[22]^[23] and alterations of aspartic acid residues.^[14]^[24] In turn these events have a profound effect on the mechanical properties of ECM proteins.^[25]

Various molecular models are proposed to rationalize the molecular basis of skin aging, mostly including the overall recognized aging mechanisms such as cellular senescence, telomere shortening, decrease in cellular DNA repair capacity and point mutations of extranuclear mitochondrial DNA, oxidative stress, chromosomal abnormalities, gene mutations, and chronic inflammation (inflammaging).^[25]

While skin aging is a natural process that cannot be completely prevented, there are steps that can be taken to slow the process and maintain healthy skin. These include protecting the skin from UV radiation by wearing protective clothing and using sunscreen, avoiding smoking and exposure to pollution, and maintaining a healthy diet and lifestyle. Additionally, skincare products that contain ingredients such as retinoids, antioxidants, and hyaluronic acid can help decrease the appearance of fine lines and wrinkles, improve skin texture and tone, and enhance hydration. Generally, the strategies for treating skin aging include the common antiaging approaches: stem cell therapy, hormone replacement therapy, telomere modification, diet restriction, and also antioxidant, retinoid, and anti-inflammaging treatments.^[25]

In addition to its social and health-related implications, skin aging is also an area of interest for the cosmetics and skincare industries. There is a large market for antiaging skincare products, and research into the underlying mechanisms of skin aging can help to develop new and more effective products.

References

↑ ^1.0 ^1.1 Gilchrest BA: Skin aging and photoaging: an overview. J Am Acad Dermatol 1989. (PMID 2476468) [PubMed] [DOI] As the population ages, common skin disorders of the elderly demand greater attention. Moreover, the many clinical, histologic, and physiologic changes that characterize old skin are increasingly implicated in its vulnerability to environmental injury and certain diseases. Thus it behooves dermatologists to study the basic biologic process of aging in the skin and the separable process of photoaging, which itself is a major clinical problem. To date studies at the cellular level have demonstrated major functional losses, particularly in proliferative capacity between infancy and adulthood, with definite further loss between early and late adulthood and as a result of chronic sun exposure. Continued careful, quantitative assessment of aging and photoaging in human skin both in vivo and in vitro will be critical to a better understanding of these processes and particularly to their successful therapeutic modification.
↑ ^2.0 ^2.1 ^2.2 Yaar M et al.: Fifty years of skin aging. J Investig Dermatol Symp Proc 2002. (PMID 12518793) [PubMed] [DOI] In developed countries, interest in cutaneous aging is in large part the result of a progressive, dramatic rise over the past century in the absolute number and the proportion of the population who are elderly (Smith et al, 2001). The psychosocial as well as physiologic effects of skin aging on older individuals have created a demand for better understanding of the process and particularly for effective interventions. Skin aging is a complex process determined by the genetic endowment of the individual as well as by environmental factors. The appearance of old skin and the clinical consequences of skin aging have been well known for centuries, but only in the past 50 y have mechanisms and mediators been systematically pursued. Still, within this relatively short time there has been tremendous progress, a progress greatly enhanced by basic gerontologic research employing immunologic, biochemical, and particularly molecular biologic approaches (Figs 1, 2).
↑ Griffiths CE et al.: A photonumeric scale for the assessment of cutaneous photodamage. Arch Dermatol 1992. (PMID 1550366) [PubMed] BACKGROUND AND DESIGN: The assessment of the severity of cutaneous photodamage and its response to treatment is an impractical consideration for most practitioners without extensive experience or recourse to high-quality, standardized, baseline photographs. To address this problem, a nine-point photonumeric standard scale was developed using photographs of subjects representing grades of photodamage from none to severe. This scale was formally tested in a side-by-side comparison with a conventional and widely used written descriptive scale. A panel of seven graders used both scales to score two sets of 25 photographs of photodamaged individuals, and the intergrader agreement and repeatability for the scales were calculated. RESULTS: The photonumeric scale demonstrated significantly greater agreement between graders than did the descriptive scale (chance-corrected agreements of 0.31 and 0.11, respectively, P less than .0001) with no significant difference in repeatability between the two methods. CONCLUSIONS: This study demonstrates that the photonumeric standard scale is superior to existing methodology in the accurate assessment of cutaneous photodamage and would be a useful adjunct to studies of the efficacy of skin repair agents for this indication.
↑ Larnier C et al.: Evaluation of cutaneous photodamage using a photographic scale. Br J Dermatol 1994. (PMID 8123569) [PubMed] [DOI] Clinical assessments of photodamage are based upon a subjective evaluation of characteristic features such as wrinkling and pigmentary change, and are influenced by inter-observer differences in grading criteria. In an effort to standardize the grading of photodamage severity, we have developed a six-point photographic scale in which each of the six grades of overall photodamage severity is depicted by three photographs. The use of three photographs to portray each grade illustrates the diversity and range of manifestations within each grade. This photographic scale was tested by two groups of dermatologists, who used it on two occasions to grade the overall photodamage severity of a single group of female Caucasian subjects. Results indicate high inter-observer agreement, with chance-corrected agreement ranging from 0.44 to 0.63 and from 0.54 to 0.76 on the first and second occasions, respectively. Intra-observer repeatability was high, with chance-corrected agreement ranging from 0.56 to 0.78. Inter- and intra-observer differences were within one category in nearly all cases. Similar grades were assigned by dermatologists with and without experience in treating photodamaged patients. We conclude that application of this scale results in consistent and reproducible clinical evaluations of overall photodamage severity in Caucasian subjects. The scale may be useful in categorizing subjects for epidemiological studies, or in selecting patients for clinical trials.
↑ Vierkötter A et al.: The SCINEXA: a novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing. J Dermatol Sci 2009. (PMID 19059763) [PubMed] [DOI] BACKGROUND: Studies on the pathogenesis of skin ageing as well as efficacy testing of cosmetic and aesthetic measures to prevent or reverse skin ageing require - as an easy to use method - a validated non-invasive clinical score, which allows to simultaneously assess and differentiate between intrinsic (=chronological) and extrinsic (=photo-) skin ageing. Such an ideal score, however, does currently not exist. OBJECTIVES: We developed a novel skin ageing score 'SCINEXA' comprising 5 items indicative of intrinsic and 18 items highly characteristic of extrinsic skin ageing. These items were used to define an index (index(discr)) that allowed differentiating between intrinsic versus extrinsic skin ageing. In order to validate the 'SCINEXA', we asked whether it can be used to discriminate regular sunbed users, which have been chronically exposed to ultraviolet radiation and thus are prone to photoageing, from non-sunbed users, which were considered paradigmatic for intrinsic skin ageing. METHODS: For this purpose, 58 non-sunbed users and 16 regularly sunbed users were assessed. In addition to the clinical examination of the 23 score items potential confounders were considered by questionnaire. RESULTS: By employing the index(discr), we were able to classify 92% of all study subjects correctly as sunbed or non-sunbed users. Specifically, an index above 2 was associated with sunbed use and thus extrinsic skin ageing, whereas an index below 2 indicated intrinsic skin ageing. CONCLUSION: The novel 'SCINEXA' is suitable for the simultaneous assessment of intrinsic and extrinsic skin ageing.
↑ Dobos G et al.: Evaluation of skin ageing: a systematic review of clinical scales. Br J Dermatol 2015. (PMID 25363020) [PubMed] [DOI] Clinical scales are widely used in anti-ageing research and practice. More than 100 skin ageing scales exist, which makes it difficult to choose outcome measures and to compare study results. The objectives were to assess and evaluate the quality of measurement properties of available clinical skin ageing scales. A systematic review was conducted. Electronic databases including Medline (1970 to June 2013) and EMBASE (1974 to June 2013) were searched via Ovid SP. To enhance the sensitivity forward searches were conducted in Scopus and Web of Science. We identified 111 scales in 52 included publications. Thirty studies had good methodology for at least one measurement property. Forty-two scales were evaluated for their test-retest or interrater reliability. Nineteen showed high reliability coefficients. A further 15 instruments were partly supported by content and/or structural and/or criterion validity and/or hypotheses-testing evidence. The majority of existing clinical skin ageing scales were developed for evaluating facial characteristics. Many scales quantify similar constructs. In contrast to the high number of available scales there is limited evidence supporting their measurement properties. Recommendations for the use of specific skin ageing scales for clinical studies must be made with caution because of the high number of studies with poor methodology. Development of new instruments should be justified, and existing ones investigated for scale behaviour using appropriate methods. Future research should aim to select and/or adapt existing scales to identify the 'best' to improve clinical research and practice.
↑ Wong QYA & Chew FT: Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep 2021. (PMID 34764376) [PubMed] [DOI] [Full text] Skin aging has been defined to encompass both intrinsic and extrinsic aging, with extrinsic aging effected by environmental influences and overlaying the effects of chronological aging. The risk factors of skin aging have been studied previously, using methods of quantifying skin aging. However, these studies have yet to be reviewed. To better understand skin aging risk factors and collate the available data, we aimed to conduct a systematic review and meta-analysis. We conducted our systematic review in compliance with Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. Embase, PubMed and Web of Science databases were searched in October 2020 using specific search strategies. Where odds ratios were reported, meta-analyses were conducted using the random effects model. Otherwise, significant factors were reported in this review. We identified seven notable risk factors for various skin aging phenotypes: age, gender, ethnicity, air pollution, nutrition, smoking, sun exposure. This review's results will guide future works, such as those aiming to examine the interaction between genetic and environmental influences.
↑ ^8.0 ^8.1 Zhang S & Duan E: Fighting against Skin Aging: The Way from Bench to Bedside. Cell Transplant 2018. (PMID 29692196) [PubMed] [DOI] [Full text] As the most voluminous organ of the body that is exposed to the outer environment, the skin suffers from both intrinsic and extrinsic aging factors. Skin aging is characterized by features such as wrinkling, loss of elasticity, laxity, and rough-textured appearance. This aging process is accompanied with phenotypic changes in cutaneous cells as well as structural and functional changes in extracellular matrix components such as collagens and elastin. In this review, we summarize these changes in skin aging, research advances of the molecular mechanisms leading to these changes, and the treatment strategies aimed at preventing or reversing skin aging.
↑ Mora Huertas AC et al.: Molecular-level insights into aging processes of skin elastin. Biochimie 2016. (PMID 27569260) [PubMed] [DOI] Skin aging is characterized by different features including wrinkling, atrophy of the dermis and loss of elasticity associated with damage to the extracellular matrix protein elastin. The aim of this study was to investigate the aging process of skin elastin at the molecular level by evaluating the influence of intrinsic (chronological aging) and extrinsic factors (sun exposure) on the morphology and susceptibility of elastin towards enzymatic degradation. Elastin was isolated from biopsies derived from sun-protected or sun-exposed skin of differently aged individuals. The morphology of the elastin fibers was characterized by scanning electron microscopy. Mass spectrometric analysis and label-free quantification allowed identifying differences in the cleavage patterns of the elastin samples after enzymatic digestion. Principal component analysis and hierarchical cluster analysis were used to visualize differences between the samples and to determine the contribution of extrinsic and intrinsic aging to the proteolytic susceptibility of elastin. Moreover, the release of potentially bioactive peptides was studied. Skin aging is associated with the decomposition of elastin fibers, which is more pronounced in sun-exposed tissue. Marker peptides were identified, which showed an age-related increase or decrease in their abundances and provide insights into the progression of the aging process of elastin fibers. Strong age-related cleavage occurs in hydrophobic tropoelastin domains 18, 20, 24 and 26. Photoaging makes the N-terminal and central parts of the tropoelastin molecules more susceptible towards enzymatic cleavage and, hence, accelerates the age-related degradation of elastin.
↑ Krutmann J et al.: Environmentally-Induced (Extrinsic) Skin Aging: Exposomal Factors and Underlying Mechanisms. J Invest Dermatol 2021. (PMID 33541724) [PubMed] [DOI] As a barrier organ, the skin is an ideal model to study environmentally-induced (extrinsic) aging. In this review, we explain the development of extrinsic skin aging as a consequence of skin exposure to specific exposomal factors, their interaction with each other, and the modification of their effects on the skin by genetic factors. We also review the evidence that exposure to these exposomal factors causes extrinsic skin aging by mechanisms that critically involve the accumulation of macromolecular damage and the subsequent development of functionally altered and/or senescent fibroblasts in the dermal compartment of the skin.
↑ Farage MA et al.: Intrinsic and extrinsic factors in skin ageing: a review. Int J Cosmet Sci 2008. (PMID 18377617) [PubMed] [DOI] As the proportion of the ageing population in industrialized countries continues to increase, the dermatological concerns of the aged grow in medical importance. Intrinsic structural changes occur as a natural consequence of ageing and are genetically determined. The rate of ageing is significantly different among different populations, as well as among different anatomical sites even within a single individual. The intrinsic rate of skin ageing in any individual can also be dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light. Photodamage, which considerably accelerates the visible ageing of skin, also greatly increases the risk of cutaneous neoplasms. As the population ages, dermatological focus must shift from ameliorating the cosmetic consequences of skin ageing to decreasing the genuine morbidity associated with problems of the ageing skin. A better understanding of both the intrinsic and extrinsic influences on the ageing of the skin, as well as distinguishing the retractable aspects of cutaneous ageing (primarily hormonal and lifestyle influences) from the irretractable (primarily intrinsic ageing), is crucial to this endeavour.
↑ ^12.0 ^12.1 Guimarães GR et al.: Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging. Cells 2021. (PMID 34073434) [PubMed] [DOI] [Full text] The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.
↑ ^13.0 ^13.1 Shapiro SD et al.: Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J Clin Invest 1991. (PMID 2022748) [PubMed] [DOI] [Full text] Normal structure and function of the lung parenchyma depend upon elastic fibers. Amorphous elastin is biochemically stable in vitro, and may provide a metabolically stable structural framework for the lung parenchyma. To test the metabolic stability of elastin in the normal human lung parenchyma, we have (a) estimated the time elapsed since the synthesis of the protein through measurement of aspartic acid racemization and (b) modeled the elastin turnover through measurement of the prevalence of nuclear weapons-related 14C. Elastin purified by a new technique from normal lung parenchyma was hydrolyzed; then the prevalences of D-aspartate and 14C were measured by gas chromatography and accelerator-mass spectrometry, respectively. D-aspartate increased linearly with age; Kasp (1.76 x 10(-3) yr(-1) was similar to that previously found for extraordinarily stable human tissues, indicating that the age of lung parenchymal elastin corresponded with the age of the subject. Radiocarbon prevalence data also were consistent with extraordinary metabolic stability of elastin; the calculated mean carbon residence time in elastin was 74 yr (95% confidence limits, 40-174 yr). These results indicate that airspace enlargement characteristic of "aging lung" is not associated with appreciable new synthesis of lung parenchymal elastin. The present study provides the first tissue-specific evaluation of turnover of an extracellular matrix component in humans and underscores the potential importance of elastin for maintenance of normal lung structure. Most importantly, the present work provides a foundation for strategies to directly evaluate extracellular matrix injury and repair in diseases of lung (especially pulmonary emphysema), vascular tissue, and skin.
↑ ^14.0 ^14.1 Ritz-Timme S et al.: Aspartic acid racemization: evidence for marked longevity of elastin in human skin. Br J Dermatol 2003. (PMID 14632798) [PubMed] [DOI] BACKGROUND: In extracellular proteins, aspartic acid racemization (AAR) has the potential to identify long-lived or permanent proteins. OBJECTIVES: We present data to show an age-dependent increase in AAR in chronologically aged skin elastin. METHODS: Elastin was purified in a multistep procedure designed to remove contaminating proteins and to avoid induced racemization. As a control experiment, elastin was also purified from the richest elastin bearing tissue, the yellow ligaments of the spine. RESULTS: In total skin, specimens displayed a slight age-dependent increase in d-aspartyl residues, but in purified elastin the rate of increase was rapid and highly correlated with age (r = 0.98). Similar rates were observed in the control data from the yellow ligaments. The AAR rates were found to be higher in elastin from skin (and yellow ligaments) than previous studies of lung parenchyma and from aorta had shown. These differences appear to be related to the purity of the extracted elastin product, and to a significant in vivo degradation of elastin in skin. CONCLUSIONS: The age-dependent accumulation of modified aspartic acid residues appears to be a common feature in ageing elastin, independent of the tissue source. This indicates a lack of turnover and an accumulation of elastin damage in diverse ageing tissues, possibly as part of programmed ageing.
↑ ^15.0 ^15.1 Jennissen HP: Ubiquitin and the enigma of intracellular protein degradation. Eur J Biochem 1995. (PMID 7628459) [PubMed] Contrary to widespread belief, the regulation and mechanism of degradation for the mass of intracellular proteins (i.e. differential, selective protein turnover) in vertebrate tissues is still a major biological enigma. There is no evidence for the conclusion that ubiquitin plays any role in these processes. The primary function of the ubiquitin-dependent protein degradation pathway appears to lie in the removal of abnormal, misfolded, denatured or foreign proteins in some eukaryotic cells. ATP/ubiquitin-dependent proteolysis probably also plays a role in the degradation of some so-called 'short-lived' proteins. Evidence obtained from the covalent modification of such natural substrates as calmodulin, histones (H2A, H2B) and some cell membrane receptors with ubiquitin indicates that the reversible interconversion of proteins with ubiquitin followed by concomitant functional changes may be of prime importance.
↑ Bailey AJ: Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 2001. (PMID 11322995) [PubMed] [DOI] The outward manifestations of tissue ageing occurring in the elderly primarily involve the two major structural proteins of the body, collagen and elastin. The changes in these proteins are associated with intermolecular cross-linking and side-chain modifications. Cross-linking involves two different mechanisms, a precise enzymic process during development and maturation, and a subsequent non-enzymic adventitious reaction with glucose during ageing. The latter glycation reactions are the major cause of tissue dysfunction in the elderly due to cross-linking, which stiffens the tissues, and to side-chain modification, which alters normal cell-matrix interactions. Photoageing by UV involves two competing reactions, chain cleavage and cross-linking, the former predominating on long-term exposure. The molecular mechanisms involved are gradually being unravelled and will lead to the development of inhibitors of these deleterious effects of ageing.
↑ Robert L et al.: Rapid increase in human life expectancy: will it soon be limited by the aging of elastin?. Biogerontology 2008. (PMID 18175202) [PubMed] [DOI] The postponement of the most frequent age-related diseases stimulated speculations of the possibility of "dying of old age". The selective decline of individual physiological functions-aging in spare-parts-indicates however the potential limitation of the life-span by the rapid decline of some of the vital parameters. We explored a possibility of such a limitation of maximal life-span by the age-related alteration of elastin, consisting in Ca-accumulation, lipid deposition and elastolytic degradation. The quantitative evaluation of these processes suggests an approximative upper limit for the elastic properties of the cardio-respiratory system of about 100-120 years, at least, as far as elastin is involved. This process, age-related alterations of elastic fibers, is however not the only one limiting the functional value of the cardiovascular system. Crosslinking of collagen fibers by advanced glycation end-products certainly contributes also to the age-dependent rigidification of the cardiovascular system. Therefore the answer to the initial question, can age-dependent alterations of a single matrix macromolecule be limiting such vital functions as the cardio-respiratory system-is a cautious yes, with however the caveat that other, independent mechanisms, such as the Maillard reaction, can also interfere with and limit further the functional value of such vital physiological functions.
↑ Verzijl N et al.: Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 2000. (PMID 10976109) [PubMed] [DOI] Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.
↑ Davis EC: Stability of elastin in the developing mouse aorta: a quantitative radioautographic study. Histochemistry 1993. (PMID 8226106) [PubMed] [DOI] Elastic lamina growth during development and the ultimate stability of elastin in the mouse aortic media was investigated by light and electron microscopic radioautography. Following a single subcutaneous injection of L-[3,4-3H]valine at 3 days of age, animals were killed at 9 subsequent time intervals up to 4 months of age. One day after injection, radioautographic silver grains were primarily observed over the elastic laminae; however, silver grains were also seen over the smooth muscle cells and extracellular matrix. By 21 to 28 days of age, the silver grains were almost exclusively located over the elastic laminae. From 28 days to 4 months of age, the distribution of silver grains appeared relatively unchanged. Quantitation of silver grain number/micron2 of elastin showed a steady decrease in the concentration of silver grains associated with the elastic laminae from 4 to 21 days of age. After this time, no significant difference in silver grain concentration was observed. Since the initial decrease in grains/micron2 of elastin corresponds to a period of rapid post-natal growth, the decrease is likely to be a result of dilution of the radiolabel due to new elastin synthesis. With the assumption that little or no significant turnover occurs during this time, a constant growth rate of 4.3% per day was predicted by linear regression analysis. Since no significant difference in the concentration of silver grains was observed from 28 to 118 days of age, no new growth or turnover of elastin can be said to occur during this time period. This is supported by the observation that animals injected with radiolabeled valine at 28 days and 8 months of age showed no significant incorporation of radiolabel into the elastic laminae. The results from this study present the first long-term radioautographic evidence of the stability of aortic elastin and emphasize that initial deposition of elastin and proper assembly of elastic laminae is a critical event in vessel development.
↑ Rucker RB & Tinker D: Structure and metabolism of arterial elastin. Int Rev Exp Pathol 1977. (PMID 849882) [PubMed]
↑ Konova E et al.: Age-related changes in the glycation of human aortic elastin. Exp Gerontol 2004. (PMID 15036419) [PubMed] [DOI] Non-enzymatic glycation of proteins is a consequence of hyperglycemia in diabetes and correlates with aging. The aim of the study was to investigate age-related changes in the glycation of human aortic elastin in healthy subjects by two approaches: (1) assessment by fluorescence method of formed in vivo advanced glycation end products (AGEs) of elastins, purified from human aortas, obtained from different age groups; (2) in vitro glycation of elastins from different age groups and investigation of their capacity to form early (by colorimetric nitroblue tetrazolium method) and AGEs (fluorescence method). Human insoluble elastins were prepared from macro- and microscopic unaltered regions of thoracic aortas, obtained from 68 accident victims, distributed in 15 age-groups, using the method of Starcher and Galione. Soluble alpha-elastins were obtained by the method of Partridge et al. The direct assessment of Maillard reaction related fluorescence in the age groups showed increase of the fluorescence with age. The 'young' elastin had the highest capacity to form both fructosamine and AGEs under glycation in vitro. The glycation of 'old' elastin did not increase markedly during the incubation. These results are consistent with the interpretation that because of its long biological half-life, elastin is susceptible to the slow process of glycation and the following modifications would contribute to the age-related changes of connective tissue.
↑ Elliott RJ & McGrath LT: Calcification of the human thoracic aorta during aging. Calcif Tissue Int 1994. (PMID 8062142) [PubMed] [DOI] The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner, -middle, and -outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 micrograms Ca/mg tissue at 20 years of age to 5.2 micrograms Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medial calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 micrograms Ca/mg tissue at 20 years of age to 49.50 micrograms Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate than that found within the middle media.
↑ Jacotot B et al.: Role of elastic tissue in cholesterol deposition in the arterial wall. Nutr Metab 1973. (PMID 4576166) [PubMed] [DOI]
↑ Ritz-Timme S & Collins MJ: Racemization of aspartic acid in human proteins. Ageing Res Rev 2002. (PMID 12039448) [PubMed] [DOI] Aspartic acid racemization (AAR) represents one of the major types of non-enzymatic covalent modification that leads to an age-dependent accumulation of abnormal protein in numerous human tissues. In vivo racemization is an autonomic process during the "natural" ageing of proteins, and correlates with the age of long-lived proteins. Consequently AAR can be used as molecular indicator of protein ageing as well as for the identification of permanent proteins that age with the human organism. Although long-living, structural proteins are mainly affected, AAR may be significant on a time scale also relevant to enzymes and signaling proteins. It may result in a loss of protein function due to proteolysis or due to changes in the molecular structure. In vivo racemization may also increase in pathological conditions. AAR has already been discussed as a relevant pathophysiological factor in the pathogenesis of diseases of old age such as atherosclerosis, lung emphysema, presbyopia, cataract, degenerative diseases of cartilage and cerebral age-related dysfunctions. Although the details of the biological consequences of AAR have to be further elucidated, it is evident that AAR plays a role in the molecular biology of ageing.
↑ ^25.0 ^25.1 ^25.2 Naylor EC et al.: Molecular aspects of skin ageing. Maturitas 2011. (PMID 21612880) [PubMed] [DOI] Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin. The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFβ). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation.
↑ Tenchov R et al.: Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem Neurosci 2023. (PMID 38095562) [PubMed] [DOI] Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.

[pmid2476468-1] 1.0 ^1.1 Gilchrest BA: Skin aging and photoaging: an overview. J Am Acad Dermatol 1989. (PMID 2476468) [PubMed] [DOI] As the population ages, common skin disorders of the elderly demand greater attention. Moreover, the many clinical, histologic, and physiologic changes that characterize old skin are increasingly implicated in its vulnerability to environmental injury and certain diseases. Thus it behooves dermatologists to study the basic biologic process of aging in the skin and the separable process of photoaging, which itself is a major clinical problem. To date studies at the cellular level have demonstrated major functional losses, particularly in proliferative capacity between infancy and adulthood, with definite further loss between early and late adulthood and as a result of chronic sun exposure. Continued careful, quantitative assessment of aging and photoaging in human skin both in vivo and in vitro will be critical to a better understanding of these processes and particularly to their successful therapeutic modification.

[pmid12518793-2] 2.0 ^2.1 ^2.2 Yaar M et al.: Fifty years of skin aging. J Investig Dermatol Symp Proc 2002. (PMID 12518793) [PubMed] [DOI] In developed countries, interest in cutaneous aging is in large part the result of a progressive, dramatic rise over the past century in the absolute number and the proportion of the population who are elderly (Smith et al, 2001). The psychosocial as well as physiologic effects of skin aging on older individuals have created a demand for better understanding of the process and particularly for effective interventions. Skin aging is a complex process determined by the genetic endowment of the individual as well as by environmental factors. The appearance of old skin and the clinical consequences of skin aging have been well known for centuries, but only in the past 50 y have mechanisms and mediators been systematically pursued. Still, within this relatively short time there has been tremendous progress, a progress greatly enhanced by basic gerontologic research employing immunologic, biochemical, and particularly molecular biologic approaches (Figs 1, 2).

[pmid1550366-3] Griffiths CE et al.: A photonumeric scale for the assessment of cutaneous photodamage. Arch Dermatol 1992. (PMID 1550366) [PubMed] BACKGROUND AND DESIGN: The assessment of the severity of cutaneous photodamage and its response to treatment is an impractical consideration for most practitioners without extensive experience or recourse to high-quality, standardized, baseline photographs. To address this problem, a nine-point photonumeric standard scale was developed using photographs of subjects representing grades of photodamage from none to severe. This scale was formally tested in a side-by-side comparison with a conventional and widely used written descriptive scale. A panel of seven graders used both scales to score two sets of 25 photographs of photodamaged individuals, and the intergrader agreement and repeatability for the scales were calculated. RESULTS: The photonumeric scale demonstrated significantly greater agreement between graders than did the descriptive scale (chance-corrected agreements of 0.31 and 0.11, respectively, P less than .0001) with no significant difference in repeatability between the two methods. CONCLUSIONS: This study demonstrates that the photonumeric standard scale is superior to existing methodology in the accurate assessment of cutaneous photodamage and would be a useful adjunct to studies of the efficacy of skin repair agents for this indication.

[pmid8123569-4] Larnier C et al.: Evaluation of cutaneous photodamage using a photographic scale. Br J Dermatol 1994. (PMID 8123569) [PubMed] [DOI] Clinical assessments of photodamage are based upon a subjective evaluation of characteristic features such as wrinkling and pigmentary change, and are influenced by inter-observer differences in grading criteria. In an effort to standardize the grading of photodamage severity, we have developed a six-point photographic scale in which each of the six grades of overall photodamage severity is depicted by three photographs. The use of three photographs to portray each grade illustrates the diversity and range of manifestations within each grade. This photographic scale was tested by two groups of dermatologists, who used it on two occasions to grade the overall photodamage severity of a single group of female Caucasian subjects. Results indicate high inter-observer agreement, with chance-corrected agreement ranging from 0.44 to 0.63 and from 0.54 to 0.76 on the first and second occasions, respectively. Intra-observer repeatability was high, with chance-corrected agreement ranging from 0.56 to 0.78. Inter- and intra-observer differences were within one category in nearly all cases. Similar grades were assigned by dermatologists with and without experience in treating photodamaged patients. We conclude that application of this scale results in consistent and reproducible clinical evaluations of overall photodamage severity in Caucasian subjects. The scale may be useful in categorizing subjects for epidemiological studies, or in selecting patients for clinical trials.

[pmid19059763-5] Vierkötter A et al.: The SCINEXA: a novel, validated score to simultaneously assess and differentiate between intrinsic and extrinsic skin ageing. J Dermatol Sci 2009. (PMID 19059763) [PubMed] [DOI] BACKGROUND: Studies on the pathogenesis of skin ageing as well as efficacy testing of cosmetic and aesthetic measures to prevent or reverse skin ageing require - as an easy to use method - a validated non-invasive clinical score, which allows to simultaneously assess and differentiate between intrinsic (=chronological) and extrinsic (=photo-) skin ageing. Such an ideal score, however, does currently not exist. OBJECTIVES: We developed a novel skin ageing score 'SCINEXA' comprising 5 items indicative of intrinsic and 18 items highly characteristic of extrinsic skin ageing. These items were used to define an index (index(discr)) that allowed differentiating between intrinsic versus extrinsic skin ageing. In order to validate the 'SCINEXA', we asked whether it can be used to discriminate regular sunbed users, which have been chronically exposed to ultraviolet radiation and thus are prone to photoageing, from non-sunbed users, which were considered paradigmatic for intrinsic skin ageing. METHODS: For this purpose, 58 non-sunbed users and 16 regularly sunbed users were assessed. In addition to the clinical examination of the 23 score items potential confounders were considered by questionnaire. RESULTS: By employing the index(discr), we were able to classify 92% of all study subjects correctly as sunbed or non-sunbed users. Specifically, an index above 2 was associated with sunbed use and thus extrinsic skin ageing, whereas an index below 2 indicated intrinsic skin ageing. CONCLUSION: The novel 'SCINEXA' is suitable for the simultaneous assessment of intrinsic and extrinsic skin ageing.

[pmid25363020-6] Dobos G et al.: Evaluation of skin ageing: a systematic review of clinical scales. Br J Dermatol 2015. (PMID 25363020) [PubMed] [DOI] Clinical scales are widely used in anti-ageing research and practice. More than 100 skin ageing scales exist, which makes it difficult to choose outcome measures and to compare study results. The objectives were to assess and evaluate the quality of measurement properties of available clinical skin ageing scales. A systematic review was conducted. Electronic databases including Medline (1970 to June 2013) and EMBASE (1974 to June 2013) were searched via Ovid SP. To enhance the sensitivity forward searches were conducted in Scopus and Web of Science. We identified 111 scales in 52 included publications. Thirty studies had good methodology for at least one measurement property. Forty-two scales were evaluated for their test-retest or interrater reliability. Nineteen showed high reliability coefficients. A further 15 instruments were partly supported by content and/or structural and/or criterion validity and/or hypotheses-testing evidence. The majority of existing clinical skin ageing scales were developed for evaluating facial characteristics. Many scales quantify similar constructs. In contrast to the high number of available scales there is limited evidence supporting their measurement properties. Recommendations for the use of specific skin ageing scales for clinical studies must be made with caution because of the high number of studies with poor methodology. Development of new instruments should be justified, and existing ones investigated for scale behaviour using appropriate methods. Future research should aim to select and/or adapt existing scales to identify the 'best' to improve clinical research and practice.

[pmid34764376-7] Wong QYA & Chew FT: Defining skin aging and its risk factors: a systematic review and meta-analysis. Sci Rep 2021. (PMID 34764376) [PubMed] [DOI] [Full text] Skin aging has been defined to encompass both intrinsic and extrinsic aging, with extrinsic aging effected by environmental influences and overlaying the effects of chronological aging. The risk factors of skin aging have been studied previously, using methods of quantifying skin aging. However, these studies have yet to be reviewed. To better understand skin aging risk factors and collate the available data, we aimed to conduct a systematic review and meta-analysis. We conducted our systematic review in compliance with Preferred Reporting Item for Systematic Review and Meta-Analyses (PRISMA) guidelines. Embase, PubMed and Web of Science databases were searched in October 2020 using specific search strategies. Where odds ratios were reported, meta-analyses were conducted using the random effects model. Otherwise, significant factors were reported in this review. We identified seven notable risk factors for various skin aging phenotypes: age, gender, ethnicity, air pollution, nutrition, smoking, sun exposure. This review's results will guide future works, such as those aiming to examine the interaction between genetic and environmental influences.

[pmid29692196-8] 8.0 ^8.1 Zhang S & Duan E: Fighting against Skin Aging: The Way from Bench to Bedside. Cell Transplant 2018. (PMID 29692196) [PubMed] [DOI] [Full text] As the most voluminous organ of the body that is exposed to the outer environment, the skin suffers from both intrinsic and extrinsic aging factors. Skin aging is characterized by features such as wrinkling, loss of elasticity, laxity, and rough-textured appearance. This aging process is accompanied with phenotypic changes in cutaneous cells as well as structural and functional changes in extracellular matrix components such as collagens and elastin. In this review, we summarize these changes in skin aging, research advances of the molecular mechanisms leading to these changes, and the treatment strategies aimed at preventing or reversing skin aging.

[pmid27569260-9] Mora Huertas AC et al.: Molecular-level insights into aging processes of skin elastin. Biochimie 2016. (PMID 27569260) [PubMed] [DOI] Skin aging is characterized by different features including wrinkling, atrophy of the dermis and loss of elasticity associated with damage to the extracellular matrix protein elastin. The aim of this study was to investigate the aging process of skin elastin at the molecular level by evaluating the influence of intrinsic (chronological aging) and extrinsic factors (sun exposure) on the morphology and susceptibility of elastin towards enzymatic degradation. Elastin was isolated from biopsies derived from sun-protected or sun-exposed skin of differently aged individuals. The morphology of the elastin fibers was characterized by scanning electron microscopy. Mass spectrometric analysis and label-free quantification allowed identifying differences in the cleavage patterns of the elastin samples after enzymatic digestion. Principal component analysis and hierarchical cluster analysis were used to visualize differences between the samples and to determine the contribution of extrinsic and intrinsic aging to the proteolytic susceptibility of elastin. Moreover, the release of potentially bioactive peptides was studied. Skin aging is associated with the decomposition of elastin fibers, which is more pronounced in sun-exposed tissue. Marker peptides were identified, which showed an age-related increase or decrease in their abundances and provide insights into the progression of the aging process of elastin fibers. Strong age-related cleavage occurs in hydrophobic tropoelastin domains 18, 20, 24 and 26. Photoaging makes the N-terminal and central parts of the tropoelastin molecules more susceptible towards enzymatic cleavage and, hence, accelerates the age-related degradation of elastin.

[pmid33541724-10] Krutmann J et al.: Environmentally-Induced (Extrinsic) Skin Aging: Exposomal Factors and Underlying Mechanisms. J Invest Dermatol 2021. (PMID 33541724) [PubMed] [DOI] As a barrier organ, the skin is an ideal model to study environmentally-induced (extrinsic) aging. In this review, we explain the development of extrinsic skin aging as a consequence of skin exposure to specific exposomal factors, their interaction with each other, and the modification of their effects on the skin by genetic factors. We also review the evidence that exposure to these exposomal factors causes extrinsic skin aging by mechanisms that critically involve the accumulation of macromolecular damage and the subsequent development of functionally altered and/or senescent fibroblasts in the dermal compartment of the skin.

[pmid18377617-11] Farage MA et al.: Intrinsic and extrinsic factors in skin ageing: a review. Int J Cosmet Sci 2008. (PMID 18377617) [PubMed] [DOI] As the proportion of the ageing population in industrialized countries continues to increase, the dermatological concerns of the aged grow in medical importance. Intrinsic structural changes occur as a natural consequence of ageing and are genetically determined. The rate of ageing is significantly different among different populations, as well as among different anatomical sites even within a single individual. The intrinsic rate of skin ageing in any individual can also be dramatically influenced by personal and environmental factors, particularly the amount of exposure to ultraviolet light. Photodamage, which considerably accelerates the visible ageing of skin, also greatly increases the risk of cutaneous neoplasms. As the population ages, dermatological focus must shift from ameliorating the cosmetic consequences of skin ageing to decreasing the genuine morbidity associated with problems of the ageing skin. A better understanding of both the intrinsic and extrinsic influences on the ageing of the skin, as well as distinguishing the retractable aspects of cutaneous ageing (primarily hormonal and lifestyle influences) from the irretractable (primarily intrinsic ageing), is crucial to this endeavour.

[pmid34073434-12] 12.0 ^12.1 Guimarães GR et al.: Hallmarks of Aging in Macrophages: Consequences to Skin Inflammaging. Cells 2021. (PMID 34073434) [PubMed] [DOI] [Full text] The skin is our largest organ and the outermost protective barrier. Its aging reflects both intrinsic and extrinsic processes resulting from the constant insults it is exposed to. Aging in the skin is accompanied by specific epigenetic modifications, accumulation of senescent cells, reduced cellular proliferation/tissue renewal, altered extracellular matrix, and a proinflammatory environment favoring undesirable conditions, including disease onset. Macrophages (Mφ) are the most abundant immune cell type in the skin and comprise a group of heterogeneous and plastic cells that are key for skin homeostasis and host defense. However, they have also been implicated in orchestrating chronic inflammation during aging. Since Mφ are related to innate and adaptive immunity, it is possible that age-modified skin Mφ promote adaptive immunity exacerbation and exhaustion, favoring the emergence of proinflammatory pathologies, such as skin cancer. In this review, we will highlight recent findings pertaining to the effects of aging hallmarks over Mφ, supporting the recognition of such cell types as a driving force in skin inflammaging and age-related diseases. We will also present recent research targeting Mφ as potential therapeutic interventions in inflammatory skin disorders and cancer.

[pmid2022748-13] 13.0 ^13.1 Shapiro SD et al.: Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J Clin Invest 1991. (PMID 2022748) [PubMed] [DOI] [Full text] Normal structure and function of the lung parenchyma depend upon elastic fibers. Amorphous elastin is biochemically stable in vitro, and may provide a metabolically stable structural framework for the lung parenchyma. To test the metabolic stability of elastin in the normal human lung parenchyma, we have (a) estimated the time elapsed since the synthesis of the protein through measurement of aspartic acid racemization and (b) modeled the elastin turnover through measurement of the prevalence of nuclear weapons-related 14C. Elastin purified by a new technique from normal lung parenchyma was hydrolyzed; then the prevalences of D-aspartate and 14C were measured by gas chromatography and accelerator-mass spectrometry, respectively. D-aspartate increased linearly with age; Kasp (1.76 x 10(-3) yr(-1) was similar to that previously found for extraordinarily stable human tissues, indicating that the age of lung parenchymal elastin corresponded with the age of the subject. Radiocarbon prevalence data also were consistent with extraordinary metabolic stability of elastin; the calculated mean carbon residence time in elastin was 74 yr (95% confidence limits, 40-174 yr). These results indicate that airspace enlargement characteristic of "aging lung" is not associated with appreciable new synthesis of lung parenchymal elastin. The present study provides the first tissue-specific evaluation of turnover of an extracellular matrix component in humans and underscores the potential importance of elastin for maintenance of normal lung structure. Most importantly, the present work provides a foundation for strategies to directly evaluate extracellular matrix injury and repair in diseases of lung (especially pulmonary emphysema), vascular tissue, and skin.

[pmid14632798-14] 14.0 ^14.1 Ritz-Timme S et al.: Aspartic acid racemization: evidence for marked longevity of elastin in human skin. Br J Dermatol 2003. (PMID 14632798) [PubMed] [DOI] BACKGROUND: In extracellular proteins, aspartic acid racemization (AAR) has the potential to identify long-lived or permanent proteins. OBJECTIVES: We present data to show an age-dependent increase in AAR in chronologically aged skin elastin. METHODS: Elastin was purified in a multistep procedure designed to remove contaminating proteins and to avoid induced racemization. As a control experiment, elastin was also purified from the richest elastin bearing tissue, the yellow ligaments of the spine. RESULTS: In total skin, specimens displayed a slight age-dependent increase in d-aspartyl residues, but in purified elastin the rate of increase was rapid and highly correlated with age (r = 0.98). Similar rates were observed in the control data from the yellow ligaments. The AAR rates were found to be higher in elastin from skin (and yellow ligaments) than previous studies of lung parenchyma and from aorta had shown. These differences appear to be related to the purity of the extracted elastin product, and to a significant in vivo degradation of elastin in skin. CONCLUSIONS: The age-dependent accumulation of modified aspartic acid residues appears to be a common feature in ageing elastin, independent of the tissue source. This indicates a lack of turnover and an accumulation of elastin damage in diverse ageing tissues, possibly as part of programmed ageing.

[pmid7628459-15] 15.0 ^15.1 Jennissen HP: Ubiquitin and the enigma of intracellular protein degradation. Eur J Biochem 1995. (PMID 7628459) [PubMed] Contrary to widespread belief, the regulation and mechanism of degradation for the mass of intracellular proteins (i.e. differential, selective protein turnover) in vertebrate tissues is still a major biological enigma. There is no evidence for the conclusion that ubiquitin plays any role in these processes. The primary function of the ubiquitin-dependent protein degradation pathway appears to lie in the removal of abnormal, misfolded, denatured or foreign proteins in some eukaryotic cells. ATP/ubiquitin-dependent proteolysis probably also plays a role in the degradation of some so-called 'short-lived' proteins. Evidence obtained from the covalent modification of such natural substrates as calmodulin, histones (H2A, H2B) and some cell membrane receptors with ubiquitin indicates that the reversible interconversion of proteins with ubiquitin followed by concomitant functional changes may be of prime importance.

[pmid11322995-16] Bailey AJ: Molecular mechanisms of ageing in connective tissues. Mech Ageing Dev 2001. (PMID 11322995) [PubMed] [DOI] The outward manifestations of tissue ageing occurring in the elderly primarily involve the two major structural proteins of the body, collagen and elastin. The changes in these proteins are associated with intermolecular cross-linking and side-chain modifications. Cross-linking involves two different mechanisms, a precise enzymic process during development and maturation, and a subsequent non-enzymic adventitious reaction with glucose during ageing. The latter glycation reactions are the major cause of tissue dysfunction in the elderly due to cross-linking, which stiffens the tissues, and to side-chain modification, which alters normal cell-matrix interactions. Photoageing by UV involves two competing reactions, chain cleavage and cross-linking, the former predominating on long-term exposure. The molecular mechanisms involved are gradually being unravelled and will lead to the development of inhibitors of these deleterious effects of ageing.

[pmid18175202-17] Robert L et al.: Rapid increase in human life expectancy: will it soon be limited by the aging of elastin?. Biogerontology 2008. (PMID 18175202) [PubMed] [DOI] The postponement of the most frequent age-related diseases stimulated speculations of the possibility of "dying of old age". The selective decline of individual physiological functions-aging in spare-parts-indicates however the potential limitation of the life-span by the rapid decline of some of the vital parameters. We explored a possibility of such a limitation of maximal life-span by the age-related alteration of elastin, consisting in Ca-accumulation, lipid deposition and elastolytic degradation. The quantitative evaluation of these processes suggests an approximative upper limit for the elastic properties of the cardio-respiratory system of about 100-120 years, at least, as far as elastin is involved. This process, age-related alterations of elastic fibers, is however not the only one limiting the functional value of the cardiovascular system. Crosslinking of collagen fibers by advanced glycation end-products certainly contributes also to the age-dependent rigidification of the cardiovascular system. Therefore the answer to the initial question, can age-dependent alterations of a single matrix macromolecule be limiting such vital functions as the cardio-respiratory system-is a cautious yes, with however the caveat that other, independent mechanisms, such as the Maillard reaction, can also interfere with and limit further the functional value of such vital physiological functions.

[pmid10976109-18] Verzijl N et al.: Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 2000. (PMID 10976109) [PubMed] [DOI] Collagen molecules in articular cartilage have an exceptionally long lifetime, which makes them susceptible to the accumulation of advanced glycation end products (AGEs). In fact, in comparison to other collagen-rich tissues, articular cartilage contains relatively high amounts of the AGE pentosidine. To test the hypothesis that this higher AGE accumulation is primarily the result of the slow turnover of cartilage collagen, AGE levels in cartilage and skin collagen were compared with the degree of racemization of aspartic acid (% d-Asp, a measure of the residence time of a protein). AGE (N(epsilon)-(carboxymethyl)lysine, N(epsilon)-(carboxyethyl)lysine, and pentosidine) and % d-Asp concentrations increased linearly with age in both cartilage and skin collagen (p < 0.0001). The rate of increase in AGEs was greater in cartilage collagen than in skin collagen (p < 0.0001). % d-Asp was also higher in cartilage collagen than in skin collagen (p < 0.0001), indicating that cartilage collagen has a longer residence time in the tissue, and thus a slower turnover, than skin collagen. In both types of collagen, AGE concentrations increased linearly with % d-Asp (p < 0.0005). Interestingly, the slopes of the curves of AGEs versus % d-Asp, i.e. the rates of accumulation of AGEs corrected for turnover, were identical for cartilage and skin collagen. The present study thus provides the first experimental evidence that protein turnover is a major determinant in AGE accumulation in different collagen types. From the age-related increases in % d-Asp the half-life of cartilage collagen was calculated to be 117 years and that of skin collagen 15 years, thereby providing the first reasonable estimates of the half-lives of these collagens.

[pmid8226106-19] Davis EC: Stability of elastin in the developing mouse aorta: a quantitative radioautographic study. Histochemistry 1993. (PMID 8226106) [PubMed] [DOI] Elastic lamina growth during development and the ultimate stability of elastin in the mouse aortic media was investigated by light and electron microscopic radioautography. Following a single subcutaneous injection of L-[3,4-3H]valine at 3 days of age, animals were killed at 9 subsequent time intervals up to 4 months of age. One day after injection, radioautographic silver grains were primarily observed over the elastic laminae; however, silver grains were also seen over the smooth muscle cells and extracellular matrix. By 21 to 28 days of age, the silver grains were almost exclusively located over the elastic laminae. From 28 days to 4 months of age, the distribution of silver grains appeared relatively unchanged. Quantitation of silver grain number/micron2 of elastin showed a steady decrease in the concentration of silver grains associated with the elastic laminae from 4 to 21 days of age. After this time, no significant difference in silver grain concentration was observed. Since the initial decrease in grains/micron2 of elastin corresponds to a period of rapid post-natal growth, the decrease is likely to be a result of dilution of the radiolabel due to new elastin synthesis. With the assumption that little or no significant turnover occurs during this time, a constant growth rate of 4.3% per day was predicted by linear regression analysis. Since no significant difference in the concentration of silver grains was observed from 28 to 118 days of age, no new growth or turnover of elastin can be said to occur during this time period. This is supported by the observation that animals injected with radiolabeled valine at 28 days and 8 months of age showed no significant incorporation of radiolabel into the elastic laminae. The results from this study present the first long-term radioautographic evidence of the stability of aortic elastin and emphasize that initial deposition of elastin and proper assembly of elastic laminae is a critical event in vessel development.

[pmid849882-20] Rucker RB & Tinker D: Structure and metabolism of arterial elastin. Int Rev Exp Pathol 1977. (PMID 849882) [PubMed]

[pmid15036419-21] Konova E et al.: Age-related changes in the glycation of human aortic elastin. Exp Gerontol 2004. (PMID 15036419) [PubMed] [DOI] Non-enzymatic glycation of proteins is a consequence of hyperglycemia in diabetes and correlates with aging. The aim of the study was to investigate age-related changes in the glycation of human aortic elastin in healthy subjects by two approaches: (1) assessment by fluorescence method of formed in vivo advanced glycation end products (AGEs) of elastins, purified from human aortas, obtained from different age groups; (2) in vitro glycation of elastins from different age groups and investigation of their capacity to form early (by colorimetric nitroblue tetrazolium method) and AGEs (fluorescence method). Human insoluble elastins were prepared from macro- and microscopic unaltered regions of thoracic aortas, obtained from 68 accident victims, distributed in 15 age-groups, using the method of Starcher and Galione. Soluble alpha-elastins were obtained by the method of Partridge et al. The direct assessment of Maillard reaction related fluorescence in the age groups showed increase of the fluorescence with age. The 'young' elastin had the highest capacity to form both fructosamine and AGEs under glycation in vitro. The glycation of 'old' elastin did not increase markedly during the incubation. These results are consistent with the interpretation that because of its long biological half-life, elastin is susceptible to the slow process of glycation and the following modifications would contribute to the age-related changes of connective tissue.

[pmid8062142-22] Elliott RJ & McGrath LT: Calcification of the human thoracic aorta during aging. Calcif Tissue Int 1994. (PMID 8062142) [PubMed] [DOI] The rate of calcification within the human thoracic aorta from completion of body growth to advanced old age was examined. Fifty-eight aortae, obtained at necropsy, were dissected into four layers: the complete intima and the separated media, which was subdivided into three tissue samples of equal thickness, defined as the media-inner, -middle, and -outer layers. The sampling sites selected for analysis were from regions of the aortic surface that were free of atherosclerotic plaques. The calcium content within each tissue layer of the aorta was determined. Arterial wall thickness and the cholesterol content of the four layers were also measured. Intimal calcification increased progressively during aging: from 1.6 micrograms Ca/mg tissue at 20 years of age to 5.2 micrograms Ca/mg tissue by 90 years of age. When intima calcium concentration was expressed by tissue volume (w/v), no significant change during aging was found. Medial calcification, as w/v and by w/w, increased throughout aging. Calcium accumulation was most marked in the middle, elastin-rich layer of the media, increasing from 1.4 micrograms Ca/mg tissue at 20 years of age to 49.50 micrograms Ca/mg tissue by 90 years of age. Calcium levels also increased in the other media layers, but at a slower rate than that found within the middle media.

[pmid4576166-23] Jacotot B et al.: Role of elastic tissue in cholesterol deposition in the arterial wall. Nutr Metab 1973. (PMID 4576166) [PubMed] [DOI]

[pmid12039448-24] Ritz-Timme S & Collins MJ: Racemization of aspartic acid in human proteins. Ageing Res Rev 2002. (PMID 12039448) [PubMed] [DOI] Aspartic acid racemization (AAR) represents one of the major types of non-enzymatic covalent modification that leads to an age-dependent accumulation of abnormal protein in numerous human tissues. In vivo racemization is an autonomic process during the "natural" ageing of proteins, and correlates with the age of long-lived proteins. Consequently AAR can be used as molecular indicator of protein ageing as well as for the identification of permanent proteins that age with the human organism. Although long-living, structural proteins are mainly affected, AAR may be significant on a time scale also relevant to enzymes and signaling proteins. It may result in a loss of protein function due to proteolysis or due to changes in the molecular structure. In vivo racemization may also increase in pathological conditions. AAR has already been discussed as a relevant pathophysiological factor in the pathogenesis of diseases of old age such as atherosclerosis, lung emphysema, presbyopia, cataract, degenerative diseases of cartilage and cerebral age-related dysfunctions. Although the details of the biological consequences of AAR have to be further elucidated, it is evident that AAR plays a role in the molecular biology of ageing.

[pmid21612880-25] 25.0 ^25.1 ^25.2 Naylor EC et al.: Molecular aspects of skin ageing. Maturitas 2011. (PMID 21612880) [PubMed] [DOI] Ageing of human skin may result from both the passage of time (intrinsic ageing) and from cumulative exposure to external influences (extrinsic ageing) such as ultraviolet radiation (UVR) which promote wrinkle formation and loss of tissue elasticity. Whilst both ageing processes are associated with phenotypic changes in cutaneous cells, the major functional manifestations of ageing occur as a consequence of structural and compositional remodeling of normally long-lived dermal extracellular matrix proteins. This review briefly considers the effects of ageing on dermal collagens and proteoglycans before focusing on the mechanisms, functional consequences and treatment of elastic fibre remodeling in ageing skin. The early stages of photoageing are characterised by the differential degradation of elastic fibre proteins and whilst the activity of extracellular matrix proteases is increased in photoexposed skin, the substrate specificity of these enzymes is low. We have recently shown however, that isolated fibrillin microfibrils are susceptible to direct degradation by physiologically attainable doses of UV-B radiation and that elastic fibre proteins as a group are highly enriched in UV-absorbing amino acid residues. Functionally, elastic fibre remodeling events may adversely impact on: the mechanical properties of tissues, the recruitment and activation of immune cells, the expression of matrix metalloproteinases and cytokine signaling (by perturbing fibrillin microfibril sequestration of TGFβ). Finally, newly developed topical interventions appear to be capable of regenerating elements of the elastic fibre system in ageing skin, whilst systemic treatments may potentially prevent the pathological tissue remodeling events which occur in response to elastic fibre degradation.

[pmid38095562-26] Tenchov R et al.: Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem Neurosci 2023. (PMID 38095562) [PubMed] [DOI] Aging is a dynamic, time-dependent process that is characterized by a gradual accumulation of cell damage. Continual functional decline in the intrinsic ability of living organisms to accurately regulate homeostasis leads to increased susceptibility and vulnerability to diseases. Many efforts have been put forth to understand and prevent the effects of aging. Thus, the major cellular and molecular hallmarks of aging have been identified, and their relationships to age-related diseases and malfunctions have been explored. Here, we use data from the CAS Content Collection to analyze the publication landscape of recent aging-related research. We review the advances in knowledge and delineate trends in research advancements on aging factors and attributes across time and geography. We also review the current concepts related to the major aging hallmarks on the molecular, cellular, and organismic level, age-associated diseases, with attention to brain aging and brain health, as well as the major biochemical processes associated with aging. Major age-related diseases have been outlined, and their correlations with the major aging features and attributes are explored. We hope this review will be helpful for apprehending the current knowledge in the field of aging mechanisms and progression, in an effort to further solve the remaining challenges and fulfill its potential.

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Skin Aging

Further Reading

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References