Development Of Age-associated Diseases Research Articles

T-cell immunity against senescence: potential role and perspectives.

The development of age-associated diseases is related to the accumulation of senescent cells in the body. These are old non-functional cells with impaired metabolism, which are unable to divide. Such cells are also resistant to programmed cell death and prone to spontaneous production of some inflammatory factors. The accumulation of senescent cells is related to the age-associated dysfunction of organs and tissues as well as chronic inflammation that enhances with age. In the young organism, senescent cells are removed with the innate immunity system. However, the efficiency of this process decreases with age. Nowadays, more and more evidences are accumulating to support the involvement of specific immunity and T-lymphocytes in the fight against senescent cells. It has great physiological importance since the efficient elimination of senescent cells requires a high diversity of antigen-recognizing receptors to cover the entire spectrum of senescent-associated antigens with high precision and specificity. Developing the approaches of T-cell immunity stimulation to generate or amplify a physiological immune response against senescent cells can provide new perspectives to extend active longevity. In this mini-review, the authors summarize the current understanding of the role of T-cell immunity in the fight against senescent cells and discuss the prospects of stimulating adaptive immunity for combating the accumulation of senescent cells that occurs with age.

Genetics of healthy aging and longevity

With the increase in life expectancy, there is an increase in the number of elderly people among the population, therefore, an important task for Russian health care is to ensure healthy aging. An examination of a group of centenarians can help in studying the factors and causes that contribute to a long life without development or with the later development of age-associated diseases. In many ways, the long life expectancy and better health of such people are genetically determined. At the same time, longevity, as a complex sign, is influenced by many genetic polymorphisms, often with a small individual effect. Identification of hereditary determinants and their effects on the mechanisms of aging is necessary to identify the foundations of healthy longevity and to find protector mechanisms and targets by which it is possible to prevent the occurrence or slow the progression of age-related diseases.The pathology of the cardiovascular system is the most significant of the diseases associated with aging, since it is the leading cause of mortality according to world statistics. Thus, cardiovascular aging is an important factor in determining a person’s life expectancy.This article examines the methodological aspects of studies involving centenarians, and also provides an overview of genes that affect both life expectancy and longevity, as well as the development and course of cardiovascular diseases.

Correlations between biomarkers of senescent cell accumulation at the systemic, tissue and cellular levels in elderly patients

The aim of the study was to investigate the relationship between established clinical systemic biomarkers of ageing and the development of age-associated diseases and senescent cell biomarkers at tissue and cellular levels.Thirty-eight patients (mean age 70 ± 4.9 years) who were assessed for traditional risk factors for cardiovascular diseases were included. From all patients we obtained biomaterials (peripheral blood, skin, subcutaneous fatty tissue) and isolated different cell types (peripheral blood mononuclear cells (PBMC), fibroblasts (FB) and mesenchymal stem/stromal cells (MSC)). Isolated cells were analyzed using several senescent cells biomarkers such as telomere length and telomerase activity, proliferation rate, cell cycle inhibitor expression (p16 and p21), b-galactosidase activity, gH2AX expression. CD34+ cell content in peripheral blood was determined by flow cytometry. Systemic senescent cell-associated factors (insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF-21), osteoprogerin, ferritin, soluble vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule 1 (ICAM-1)) in peripheral blood as well as senescence-associated secretory phenotype (SASP) components in MSC and FB secretome were evaluated by ELISA. Skin and adipose tissue biopsy samples were analyzed histologically to assess senescent cell markers.A strong significant association of tissue p16 expression with age (r = 0.600, p < 0.001), pulse wave velocity (PWV) (r = 0.394, p = 0.015), vascular cell adhesion molecule (VCAM-1) content (r = 0.312, p = 0.006) in the systemic blood stream and p16 mRNA level in the blood mononuclear cells (MNCs) (r = 0.380, p = 0.046) were confirmed by correlation analysis. Statistically significant correlations were found with indicators of FBs and MSCs proliferation in culture and acquisition of SASP by the cells. Thus, p16 expression in tissues correlated significantly with interleukin-6 (IL-6) (r = 0.485, p < 0.05) and monocyte chemoattractant protein type 1 (MCP-1) (r = 0.372, p < 0.05) secretion by isolated cells. The results of regression analysis confirmed that, regardless of age, the expression of p16 was associated with the proliferation of isolated cells and IL-6 within SASP. Based on these findings, two models have been proposed to predict the level of p16 expression in tissues from the levels of other markers of senescent cell accumulation determined by non-invasive methods and available in clinical practice.

Immuno(T)herapy for age-related diseases.

During the last decade, the stimulation of T-cell function by the blockage of immunosuppressive checkpoints has experienced an outstanding impact in the treatment of cancer. Development of the chimeric antigen receptor T-cell technology has also emerged as a powerful alternative for patients suffering from oncological processes, especially those affected by hematological neoplasms. Recent evidence suggest that the use of immunotherapy could be extended to non-oncological diseases and could be especially relevant for age-associated disorders, opening exciting therapeutic options for a wide range of diseases of the elderly. Here we comment on the emergence of T-cell-based immunotherapies as feasible approaches that could revolutionize the future of GeroScience.

Calorie Restriction-Regulated Molecular Pathways and Its Impact on Various Age Groups: An Overview.

Calorie restriction (CR) if planned properly with regular exercise at different ages can result in healthy weight loss. CR can also have different beneficial effects on improving lifespan and decreasing the age-associated diseases by regulating physiological, biochemical, and molecular markers. The different pathways regulated by CR include:(1) AMP-activated protein kinase (AMPK), which involves PGC-1α, SIRT1, and SIRT3. AMPK also effects myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor delta, and peroxisome proliferator-activated receptor alpha, which are involved in mitochondrial biogenesis and lipid oxidation; (2) Forkhead box transcription factor's signaling is related to the DNA repair, lipid metabolism, protection of protein structure, autophagy, and resistance to oxidative stress; (3) Mammalian target of rapamycin (mTOR) signaling, which involves key factors, such as S6 protein kinase-1 (S6K1), mTOR complex-1 (mTORC1), and 4E-binding protein (4E-BP). Under CR conditions, AMPK activation and mTOR inhibition helps in the activation of Ulk1 complex along with the acetyltransferase Mec-17, which is necessary for autophagy; (4) Insulin-like growth factor-1 (IGF-1) pathway downregulation protects against cancer and slows the aging process; (5) Nuclear factor kappa B pathway downregulation decreases the inflammation; and (6) c-Jun N-terminal kinase and p38 kinase regulation as a response to the stress. The acute and chronic CR both shows antidepression and anxiolytic action by effecting ghrelin/GHS-R1a signaling. CR also regulates GSK3β kinase and protects against age-related brain atrophy. CR at young age may show many deleterious effects by effecting different mechanisms. Parental CR before or during conception will also affect the health and development of the offspring by causing many epigenetic modifications that show transgenerational transmission. Maternal CR is associated with intrauterine growth retardation effecting the offspring in their adulthood by developing different metabolic syndromes. The epigenetic changes with response to paternal food supply also linked to offspring health. CR at middle and old age provides a significant preventive impact against the development of age-associated diseases.

Adipose tissue, immune aging, and cellular senescence.

Obesity represents a serious health problem as it is rapidly increasing worldwide. Obesity is associated with reduced healthspan and lifespan, decreased responses to infections and vaccination, and increased frequency of inflammatory conditions typical of old age. Obesity is characterized by increased fat mass and remodeling of the adipose tissue (AT). In this review, we summarize published data on the different types of AT present in mice and humans, and their roles as fat storage as well as endocrine and immune tissues. We review the age-induced changes, including those in the distribution of fat in the body, in abundance and function of adipocytes and their precursors, and in the infiltration of immune cells from the peripheral blood. We also show that cells with a senescent-associated secretory phenotype accumulate in the AT of mice and humans with age, where they secrete several factors involved in the establishment and maintenance of local inflammation, oxidative stress, cell death, tissue remodeling, and infiltration of pro-inflammatory immune cells. Not only adipocytes and pre-adipocytes but also immune cells show a senescent phenotype in the AT. With the increase in human lifespan, it is crucial to identify strategies of intervention and target senescent cells in the AT to reduce local and systemic inflammation and the development of age-associated diseases. Several studies have indeed shown that senescent cells can be effectively targeted in the AT by selectively removing them or by inhibiting the pathways that lead to the secretion of pro-inflammatory factors.

Caveolin-1, a master regulator of cellular senescence.

Cellular senescence is a feature of most somatic cells. It is characterized by an irreversible cell cycle arrest and by the ability to secrete a plethora of mediators of inflammation and growth factors, which can alter the senescent cell's microenvironment. Senescent cells accumulate in tissues over time and contribute to both aging and the development of age-associated diseases. Senescent cells have antagonistic pleiotropic roles in cancer. Given the inability of senescent cells to proliferate, cellular senescence is a powerful tumor suppressor mechanism in young individuals. However, accumulation of senescent stromal cells during aging can fuel cancer cell growth in virtue of their capacity to release factors that stimulate cell proliferation. Caveolin-1 is a structural protein component of caveolae, invaginations of the plasma membrane involved in a variety of cellular processes, including signal transduction. Mounting evidence over the last 10-15years has demonstrated a central role of caveolin-1 in the development of a senescent phenotype and the regulation of both the anti-tumorigenic and pro-tumorigenic properties of cellular senescence. In this review, we discuss the cellular mechanisms and functions of caveolin-1 in the context of cellular senescence and their relevance to the biology of cancer.

CIRCADIAN PATTERNS OF FREE-WHEEL RUNNING IN YOUNG AND OLD MICE

The mammalian circadian clock operates on a 24-hour cycle and regulates physiological, endocrine, and metabolic responses to changes in the environment. Aging disrupts this circadian process, increasing risk for development of age-associated diseases. Free-wheel running is not only an indicator of circadian rhythm, but also a strong predictor of survival from age-related diseases (i.e. cardiovascular disease). Thus, understanding the impact of age on free-wheel running can lead to a better understanding of disease progression. We analyzed free wheel running in both male and female C57BL/6J mice at young (3-6 months) and old (18-21 months) ages exposed to standard 12h light/dark cycle. Running wheel data was recorded hourly for 10 days. As expected, young female mice ran more than male mice, and old mice ran less than young mice. Regulation of wheel running demonstrated that older mice of both sexes had a delayed start time in activity patterns. Young mice began running immediately at lights off (signaling the start of their active period) and ran consistently throughout the dark phase with peak activity in the first 2 hours. In contrast, older mice had a delayed response to light with peak activity not occurring until hours 4-6 of the dark cycle and nightly activity ending 2 hours before lights on. Ongoing work will assess the central (brain) and peripheral (muscle, cardiac) regulation of free-wheel running in aging. Together, we demonstrate the importance of studying molecular mechanisms underlying circadian misalignment in older individuals to identify ways to combat age-associated disease with circadian misalignment.

The Mitochondria-Endoplasmic Reticulum Contacts and Their Critical Role in Aging and Age-Associated Diseases.

The recent discovery of interconnections between the endoplasmic reticulum (ER) membrane and those of almost all the cell compartments is providing novel perspectives for the understanding of the molecular events underlying cellular mechanisms in both physiological and pathological conditions. In particular, growing evidence strongly supports the idea that the molecular interactions occurring between ER and mitochondrial membranes, referred as the mitochondria (MT)–ER contacts (MERCs), may play a crucial role in aging and in the development of age-associated diseases. As emerged in the last decade, MERCs behave as signaling hubs composed by structural components that act as critical players in different age-associated disorders, such as neurodegenerative diseases and motor disorders, cancer, metabolic syndrome, as well as cardiovascular diseases. Age-associated disorders often derive from mitochondrial or ER dysfunction as consequences of oxidative stress, mitochondrial DNA mutations, accumulation of misfolded proteins, and defective organelle turnover. In this review, we discuss the recent advances associating MERCs to aging in the context of ER–MT crosstalk regulating redox signaling, ER-to MT lipid transfer, mitochondrial dynamics, and autophagy.

Telomere length and cardiovascular diseases

Human telomere length shortens with aging and limits the number of cell divisions (Hayflick limit). This phenomenon is believed to be an evolutionary compromise to prevent the risk of cancer. However, the shortening of telomeres can play an important role in the development of age-associated diseases in the modem society with significantly increased life expectancy and, particularly, cardiovascular diseases, causing 35% of deaths among the elderly. The review provides the latest data from the studies aimed at determining the role of telomeres in the risk of developing cardiovascular diseases and describing the factors affecting the telomere length as well as possible causes of genomic instability due to the damage of telomeric regions.

Place of vitamin D in the prevention of premature aging and the development of age-associated diseases

There is an ongoing search for the molecular and biochemical mechanisms underlying the development of aging and age-associated diseases. At the same time there is growing evidence geroprotective properties of vitamin D.In this review, described in detail the possible mechanisms by which vitamin D affects differentiation, cell proliferation and apoptosis, and describes the potential benefits of this vitamin in the fight against aging and age-related diseases.

Place of vitamin D in the prevention of premature aging and the development of age-associated diseases.

There is an ongoing search for the molecular and biochemical mechanisms underlying the development of aging and age-associated diseases. At the same time there is growing evidence geroprotective properties of vitamin D. In this review, described in detail the possible mechanisms by which vitamin D affects differentiation, cell proliferation and apoptosis, and describes the potential benefits of this vitamin in the fight against aging and age-related diseases.

Diminished stress resistance and defective adaptive homeostasis in age-related diseases.

Adaptive homeostasis is defined as the transient expansion or contraction of the homeostatic range following exposure to subtoxic, non-damaging, signaling molecules or events, or the removal or cessation of such molecules or events (Mol. Aspects Med. (2016) 49, 1-7). Adaptive homeostasis allows us to transiently adapt (and then de-adapt) to fluctuating levels of internal and external stressors. The ability to cope with transient changes in internal and external environmental stress, however, diminishes with age. Declining adaptive homeostasis may make older people more susceptible to many diseases. Chronic oxidative stress and defective protein homeostasis (proteostasis) are two major factors associated with the etiology of age-related disorders. In the present paper, we review the contribution of impaired responses to oxidative stress and defective adaptive homeostasis in the development of age-associated diseases.

Early nutrition and ageing: can we intervene?

Ageing, a complex process that results in progressive decline in intrinsic physiological function leading to an increase in mortality rate, has been shown to be affected by early life nutrition. Accumulating data from animal and epidemiological studies indicate that exposure to a suboptimal nutritional environment during fetal life can have long-term effects on adult health. In this paper, we discuss the impact of early life nutrition on the development of age-associated diseases and life span. Special emphasis is given to studies that have investigated the molecular mechanisms underlying these effects. These include permanent structural and cellular changes including epigenetics modifications, oxidative stress, DNA damage and telomere shortening. Potential strategies targeting these mechanisms, in order to prevent or alleviate the detrimental effects of suboptimal early nutrition on lifespan and age-related diseases, are also discussed. Although recent reports have already identified effective therapeutic interventions, such as antioxidant supplementation, further understanding of the extent and nature of how early nutrition influences the ageing process will enable the development of novel and more effective approaches to improve health and extend human lifespan in the future.

Oxidative stress, cellular senescence and ageing

Almost a half century ago, the free radical theory of ageing proposed that the reactive oxygen species (ROS) is a key component which contributes to the pathophysiology of ageing in mammalian cells. Over the years, numerous studies have documented the role of oxidative stress caused by ROS in the ageing process of higher organisms. In particular, several age-associated disease models suggest that ROS and oxidative stress modulate the incidence of age-related pathologies, and that it can strongly influence the ageing process and possibly lifespan. The exact mechanism of ROS and oxidative stress-induced age-related pathologies is not yet very clear. Damage to biological macromolecules caused by ROS is thought to result in many age-related chronic diseases. At the cellular level, increased ROS leads to cellular senescence among other cellular fates including apoptosis, necrosis and autophagy. Cellular senescence is a stable growth arrest phase of cells characterized by the secretion of senescence-associated secretory phenotype (SASP) factors. Recent evidence suggests that cellular senescence via its growth arrest phenotype and SASP factors is a strong contributing factor in the development of age-associated diseases. In addition, we suggest that SASP factors play an important role in the maintenance of age-associated pathologies via a positive feedback mechanism. This review aims to provide an overview of ROS mechanics and its possible role in the ageing process via induction of cellular senescence.

Endothelial signaling molecules in the development of age-associated diseases

Data on endothelial signaling molecules involved in homeostasis regulation and development of age-associated disorders are summarized. Regulation of the endothelium function is implemented by a system of signaling molecules: NO, NO synthase, prostacyclin, thrombomodulin, thromboxane, antithrombin, endothelins, fibronectin, von Willebrand factor, etc. Changes in their synthesis can cause arterial hypertension, atherosclerosis, ischemic heart disease, myocardial infarction, and other age-related disorders. Study of the molecular mechanisms mediating endothelial functioning is essential for developing new methods of diagnostics and a treatment for age-associated cardiovascular diseases.

The aging clock and circadian control of metabolism and genome stability.

It is widely accepted that aging is characterized by a gradual decline in the efficiency and accuracy of biological processes, leading to deterioration of physiological functions and development of age-associated diseases. Age-dependent accumulation of genomic instability and development of metabolic syndrome are well-recognized components of the aging phenotype, both of which have been extensively studied. Existing findings strongly support the view that the integrity of the cellular genome and metabolic function can be influenced by light at night (LAN) and associated suppression of circadian melatonin production. While LAN is reported to accelerate aging by promoting age-associated carcinogenesis in several animal models, the specific molecular mechanism(s) of its action are not fully understood. Here, we review literature supporting a connection between LAN-induced central circadian disruption of peripheral circadian rhythms and clock function, LINE-1 retrotransposon-associated genomic instability, metabolic deregulation, and aging. We propose that aging is a progressive decline in the stability, continuity, and synchronization of multi-frequency oscillations in biological processes to a temporally disorganized state. By extension, healthy aging is the ability to maintain the most consistent, stable, and entrainable rhythmicity and coordination of these oscillations, at the molecular, cellular, and systemic levels.

The role of protein clearance mechanisms in organismal ageing and age-related diseases.

The ability to maintain a functional proteome, or proteostasis, declines during the ageing process. Damaged and misfolded proteins accumulate with age, impairing cell function and tissue homeostasis. The accumulation of damaged proteins contributes to multiple age-related diseases such as Alzheimer's, Parkinson's or Huntington's disease. Damaged proteins are degraded by the ubiquitin-proteasome system or through autophagy-lysosome, key components of the proteostasis network. Modulation of either proteasome activity or autophagic-lysosomal potential extends lifespan and protects organisms from symptoms associated with proteostasis disorders, suggesting that protein clearance mechanisms are directly linked to ageing and age-associated diseases.

Healthy aging: what can we learn from Caenorhabditis elegans?

The microscopic worm Caenorhabditis elegans (C.elegans) is one of the most prominent animal models for aging studies. This is underscored by the fact that most of the genes and interventions that modulate the aging process, such as the insulin/IGF pathway, caloric restriction and mitochondrial signalling, were first identified in this organism. Remarkably, many features of the mammalian aging process are recapitulated in C.elegans: over time, damage to macromolecule accumulates, structural cellular components progressively deteriorate, physiological functions decline, resistance to stress and infections decreases, while morbidity and mortality rates increase. In humans, age represents risk factor number one for most diseases ultimately leading to death in industrialized countries, namely cardiovascular diseases, cancer and neurodegenerative disorders. Genes regulating aging in C.elegans are evolutionarily conserved and their deregulation is often involved in the development of age-associated diseases in humans. It is therefore likely that any intervention that extends C.elegans lifespan will indicate strategies to positively impact on healthy human longevity.

The sirtuin inhibitor cambinol impairs MAPK signaling, inhibits inflammatory and innate immune responses and protects from septic shock

Sirtuins (SIRT1-7) are NAD+-dependent histone deacetylases (HDACs) that play an important role in the control of metabolism and proliferation and the development of age-associated diseases like oncologic, cardiovascular and neurodegenerative diseases. Cambinol was originally described as a compound inhibiting the activity of SIRT1 and SIRT2, with efficient anti-tumor activity in vivo. Here, we studied the effects of cambinol on microbial sensing by mouse and human immune cells and on host innate immune responses in vivo. Cambinol inhibited the expression of cytokines (TNF, IL-1β, IL-6, IL-12p40, and IFN-γ), NO and CD40 by macrophages, dendritic cells, splenocytes and whole blood stimulated with a broad range of microbial and inflammasome stimuli. Sirtinol, an inhibitor of SIRT1 and SIRT2 structurally related to cambinol, also decreased macrophage response to TLR stimulation. On the contrary, selective inhibitors of SIRT1 (EX-527 and CHIC-35) and SIRT2 (AGK2 and AK-7) used alone or in combination had no inhibitory effect, suggesting that cambinol and sirtinol act by targeting more than just SIRT1 and SIRT2. Cambinol and sirtinol at anti-inflammatory concentrations also did not inhibit SIRT6 activity in in vitro assay. At the molecular level, cambinol impaired stimulus-induced phosphorylation of MAPKs and upstream MEKs. Going well along with its powerful anti-inflammatory activity, cambinol reduced TNF blood levels and bacteremia and improved survival in preclinical models of endotoxic shock and septic shock. Altogether, our data suggest that pharmacological inhibitors of sirtuins structurally related to cambinol may be of clinical interest to treat inflammatory diseases.