Role of circulating molecules in age-related cardiovascular and metabolic disorders

Studies analyzing heterochronic parabiosis mice models showed that molecules in the blood of young mice rejuvenate aged mice. Therefore, blood-based therapies have become one of the therapeutic approaches to be considered for age-related diseases. Blood includes numerous biologically active molecules such as proteins, metabolites, hormones, miRNAs, etc. and accumulating evidence indicates some of these change their concentration with chronological aging or age-related disorders. The level of some circulating molecules showed a negative or positive correlation with all-cause mortality, cardiovascular events, or metabolic disorders. Through analyses of clinical/translation/basic research, some molecules were focused on as therapeutic targets. One approach is the supplementation of circulating anti-aging molecules. Favorable results in preclinical studies let some molecules to be tested in humans. These showed beneficial or neutral results, and some were inconsistent. Studies with rodents and humans indicate circulating molecules can be recognized as biomarkers or therapeutic targets mediating their pro-aging or anti-aging effects. Characterization of these molecules with aging, testing their biological effects, and finding mimetics of young systemic milieu continue to be an interesting and important research topic to be explored.

Trajectories of Blood Pressure in Midlife Women: Does Menopause Matter?

Background: Whether changes in blood pressure (BP) over women's midlife are more driven by chronological aging or the menopause transition (MT) has been debated. We sought to determine whether women can be classified into distinct trajectory groups based on pattern and level of systolic (SBP), diastolic blood pressure, pulse pressure (PP), and mean arterial pressure (MAP) over the MT, and to assess whether menopause-related factors predict the group and/or level of BP measures. Methods: Participants were from the Study of Women's Health Across the Nation (SWAN). Group-based trajectory modeling was used to identify women who shared distinct BP trajectories over time relative to menopause onset and to assess associations of menopause-related factors with trajectory group and/or level of BP measures. An accelerated rise relative to menopause onset suggests a menopause contribution. Results: The study included 3,302 multi-racial/ethnic women with BP measures over 17 follow-up visits (baseline age[SD]: 46.3[2.7]). Women were classified into either low, medium, or high trajectory group in each BP measure. The low SBP, PP, and MAP trajectories (in 35%, 53%, and 28% of the cohort, respectively) were rising slowly before menopause but showed a significant accelerated rise 1 year after menopause, indicating a menopause contribution. The remaining BP trajectories were rising up until menopause and either continued with the same rise or declined after menopause. A younger menopause age predicted the low SBP, PP, and MAP trajectories. A greater follicle-stimulating hormone level predicted lower SBP and PP levels, while vasomotor symptoms occurrence predicted higher SBP, PP, and MAP levels over time. Estradiol did not predict trajectory or level of any BP measure. Conclusions: Distinct BP trajectories over the MT exist that revealed a group of women whose SBP, PP, and MAP trajectories are consistent with a menopause contribution. Our findings support frequent monitoring of BP during the MT.

Accelerated biological aging in people with Down syndrome with full and segmental trisomy 21 begins in childhood as revealed by immunoglobulin G glycosylation

Cells from people with Down syndrome (DS) show faster accumulation of DNA damage and epigenetic aging marks. Causative mechanisms remain un-proven and hypotheses range from amplified chromosomal instability to actions of several supernumerary chromosome 21 genes. Plasma immunoglobulin G (IgG) glycosylation profiles are established as a reliable predictor of biological and chronological aging. We performed IgG glycan profiling of n=246 individuals with DS (208 adults and 38 children) from three European populations and compared these to age-, sex- and demography-matched general populations. We uncovered very significantly increased IgG glycosylation aging marks associated with DS. Average levels of IgG glycans without galactose (G0) and those with two galactoses (G2) as a function of age in persons with DS corresponded to levels detected in 19 years older euploid individuals. Some aging marks were significant already in children with DS. Remarkably, the IgG glycan profiles of a child with segmental duplication of only 31 genes on chromosome 21 had values similar to those of age-matched DS children, outside the normal children’s range. This is the first non-epigenetic evidence of accelerated systemic biological aging in DS, suggesting it begins very early in childhood. It points to a causative contribution of the overdose of genes in a short segment of chromosome 21, not previously linked to accelerated aging, opening a route to discovery of hitherto unrecognised mechanisms.

Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression

BackgroundBeyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.MethodsEmploying advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.ResultsHere, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.

Defining skin aging and its risk factors: a systematic review and meta-analysis

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.

The role of local retinoids in eliminating signs of skin aging

Skin aging is a complex process involving both internal (chronological aging) and external (biological aging) factors. Slowing down the proliferative and immune processes in the epidermis, reducing the activity of fibroblasts and vascularization of the dermis during chronological aging lead to thinning, dryness, hypersensitivity, vulnerability and superficial wrinkles. Exposure to ultraviolet rays, pollutants, climate, and thermal factors cause keratinocyte disorganization, enhanced melanogenesis, collagen dystrophy, solar elastosis, and disorder of microcirculation. The main signs of external skin aging are deep wrinkles, sagging, pigmentation, telangiectasia, skin neoplasms. Among the local anti-aging agents, retinoids occupy a leading place, as they eliminate the main signs of skin aging. Of the entire group of retinoids, retinoic acids are the most active. However, the possibility of skin irritation limits their use. Therapeutic and cosmetic products with retinol esters (retinol palmitate) have a minimal irritating effect and can be used both for the prevention of skin aging and the elimination of its signs. Oral use of isotretinoin as an anti-aging agent is undesirable due to the many side effects and contraindications.

UVA Exposure Combined with Glycation of the Dermis Are Two Catalysts for Skin Aging and Promotes a Favorable Environment to the Appearance of Elastosis

Skin aging is the result of superimposed intrinsic (individual) and extrinsic (e.g., UV exposure or nutrition) aging. Previous works have reported a relationship between UV irradiation and glycation in the aging process, leading, for example, to modified radical species production and the appearance of AGEs (advanced glycosylation end products) in increasing quantities, particularly glycoxidation products like pentosidine. In addition, the colocalization of AGEs and elastosis has also been observed. We first investigated the combination of the glycation reaction and UVA effects on a reconstructed skin model to explain their cumulative biological effect. We found that UVA exposure combined with glycation had the ability to intensify the response for specific markers: for example, MMP1 or MMP3 mRNA, proteases involved in extracellular matrix degradation, or proinflammatory cytokine, IL1α, protein expression. Moreover, the association of glycation and UVA irradiation is believed to promote an environment that favors the onset of an elastotic-like phenomenon: mRNA coding for elastin, elastase, and tropoelastin expression is increased. Secondly, because the damaging effects of UV radiation in vivo might be more detrimental in aged skin than in young skin due to increased accumulation of pentosidine and the exacerbation of alterations related to chronological aging, we studied the biological effect of soluble pentosidine in fibroblasts grown in monolayers. We found that pentosidine induced upregulation of CXCL2, IL8, and MMP12 mRNA expression (inflammatory and elastotic markers, respectively). Tropoelastin protein expression (elastin precursor) was also increased. In conclusion, fibroblasts in monolayers cultured with soluble pentosidine and tridimensional in vitro skin constructs exposed to the combination of AGEs and UVA promote an inflammatory state and an alteration of the dermal compartment in relation to an elastosis-like environment.

Anatomy and Histologic of Intrinsic Aging Skin

Aging is an inevitable and dynamic biological process that is characterized by the progressive deterioration of body systems and declines in physiological reserve capacity. Aging skin has distinct two types: intrinsic and extrinsic. Intrinsic changes reduce collagen production, blood flow, amount of skin lipid, and loss of rete ridges. Intrinsic aging or chronological aging is cannot be restored to the skin with characterized by sagging skin and some expression of excess wrinkling lines. Intrinsic aging changes in thickness and characteristics of the epidermis, dermis, and hypodermis. Histologically, epidermis thinner by leveling off the dermo-epidermal junction. In the dermis, collagen fibers become thicker and irregular than younger skin, reducing the elasticity of the skin, while hypodermis reduces lipid volume.

MiR-30a-5p alters epidermal terminal differentiation during aging by regulating BNIP3L/NIX-dependent mitophagy

Chronological aging is characterized by an alteration of the genes regulatory network. In human skin, epidermal keratinocytes fail to differentiate properly with aging, leading to the weakening of the epidermal function. MiR-30a is particularly overexpressed with epidermal aging, but the downstream molecular mechanisms are still uncovered. The aim of this study was to decipher the effects of miR-30a overexpression in the human epidermis, with a focus on keratinocyte differentiation. We formally identified the mitophagy receptor BNIP3L as a direct target of miR-30a. Using a 3D organotypic model of reconstructed human epidermis overexpressing miR-30a, we observed a strong reduction of BNIP3L expression in the granular layer. In human epidermal sections of skin biopsies from donors of different ages, we observed a similar pattern of BNIP3L decrease with aging. Moreover, human primary keratinocytes undergoing differentiation in vitro also showed a decreased expression of BNIP3L with age, together with a retention of mitochondria. Moreover, aging is associated with altered mitochondrial metabolism in primary keratinocytes, including decreased ATP-linked respiration. Thus, miR-30a is a negative regulator of programmed mitophagy during keratinocytes terminal differentiation, impairing epidermal homeostasis with aging.

Acetyltransferase p300 Is a Putative Epidrug Target for Amelioration of Cellular Aging-Related Cardiovascular Disease

Cardiovascular disease is the leading cause of accelerated as well as chronological aging-related human morbidity and mortality worldwide. Genetic, immunologic, unhealthy lifestyles including daily consumption of high-carb/high-fat fast food, lack of exercise, drug addiction, cigarette smoke, alcoholism, and exposure to environmental pollutants like particulate matter (PM)-induced stresses contribute profoundly to accelerated and chronological cardiovascular aging and associated life threatening diseases. All these stressors alter gene expression epigenetically either through activation or repression of gene transcription via alteration of chromatin remodeling enzymes and chromatin landscape by DNA methylation or histone methylation or histone acetylation. Acetyltransferase p300, a major epigenetic writer of acetylation on histones and transcription factors, contributes significantly to modifications of chromatin landscape of genes involved in cellular aging and cardiovascular diseases. In this review, the key findings those implicate acetyltransferase p300 as a major contributor to cellular senescence or aging related cardiovascular pathologies including vascular dysfunction, cardiac hypertrophy, myocardial infarction, cardiac fibrosis, systolic/diastolic dysfunction, and aortic valve calcification are discussed. The efficacy of natural or synthetic small molecule inhibitor targeting acetyltransferase p300 in amelioration of stress-induced dysregulated gene expression, cellular aging, and cardiovascular disease in preclinical study is also discussed.