Age-related AMP-activated protein kinase alterations: From cellular energetics to longevity

Khokhlov A.N., Klebanov A.A., Morgunova G.V.

Recently, a large number of papers have appeared that describe the successful use of various biologically active compounds (short peptides, mitochondrial antioxidants, antidiabetic biguanides, mimetics of dietary restriction, autophagy modulators, etc.) as geroprotectors. However, in our opinion, in most cases, the positive results of such studies are determined by a “successful” selection of control objects. Animals with certain abnormalities are often used for this purpose, so that any favorable effect on the corresponding pathological processes leads to an increase in their lifespan. In addition, control animals can be normal (i.e., wildtype) but placed under certain extreme conditions that can be overcome just by using certain biologically active compounds. Thus, in this case, the treatment of pathologies rather than the effect on fundamental processes of aging is observed. There is a point of view that the results of Clive McCay’s well-known experiments, which have significantly prolonged the life of rats by limiting caloric intake, were determined by the facts that, firstly, the control animals fed ad libitum (which is absolutely untypical for animals in the wild) and, secondly, Fisher-344 rats, which were used in these experiments, are short-lived. The above considerations, apparently, also apply to the gerontological experiments on cultured cells. In particular, we sometimes hear remarks from our colleagues regarding the model of “stationary phase aging” of cell cultures, which is used in our laboratory, due to the fact that most of the experiments are performed on transformed rather than normal cells. However, this approach seems to us quite justified, because the phenomenon of “stationary phase”/chronological aging is common to a wide variety of cells, including bacteria, yeasts, cyanobacteria, mycoplasmas, as well as animal and plant cells. Cells with an unlimited mitotic potential do not change either from experiment to experiment or during long-term cultivation both with and without subcultivation (within the framework of the stationary phase aging model), which cannot be said of the normal diploid fibroblasts, whose telomeres are shortened with each division. In the period from seeding to entering the stationary phase of growth, the cells divide up to ten times! We believe that, to search for effective geroprotectors that affect the fundamental mechanisms of aging, it is necessary to perform studies on “maximally healthy” animals or on “maximally stable” model systems.

Khokhlov A.N., Klebanov A.A., Morgunova G.V.

Ideas of proponents and opponents of programmed aging concerning the expediency of this phenomenon for the evolution of living organisms are briefly considered. We think that evolution has no “gerontological” purpose, because the obligate restriction of cell proliferation during the development of multicellular organisms is a factor that “automatically” triggers aging due to the accumulation of various macromolecular lesions in cells as a result of the suppression, or even complete cessation of emergence of new, intact cells. This leads to the “dilution” of stochastic damage (the most important of which is DNA damage) at the level of the entire cellular population. Some additional arguments in favor of the inexpediency of aging for both species and individuals are also listed.

Wierman M.B., Maqani N., Strickler E., Li M., Smith J.S.

ABSTRACT AMP-activated protein kinase (AMPK) and the homologous yeast SNF1 complex are key regulators of energy metabolism that counteract nutrient deficiency and ATP depletion by phosphorylating multiple enzymes and transcription factors that maintain energetic homeostasis. AMPK/SNF1 also promotes longevity in several model organisms, including yeast. Here we investigate the role of yeast SNF1 in mediating the extension of chronological life span (CLS) by caloric restriction (CR). We find that SNF1 activity is required throughout the transition of log phase to stationary phase (diauxic shift) for effective CLS extension. CR expands the period of maximal SNF1 activation beyond the diauxic shift, as indicated by Sak1-dependent T210 phosphorylation of the Snf1 catalytic α-subunit. A concomitant increase in ADP is consistent with SNF1 activation by ADP in vivo. Downstream of SNF1, the Cat8 and Adr1 transcription factors are required for full CR-induced CLS extension, implicating an alternative carbon source utilization for acetyl coenzyme A (acetyl-CoA) production and gluconeogenesis. Indeed, CR increased acetyl-CoA levels during the diauxic shift, along with expression of both acetyl-CoA synthetase genes ACS1 and ACS2. We conclude that CR maximizes Snf1 activity throughout and beyond the diauxic shift, thus optimizing the coordination of nucleocytosolic acetyl-CoA production with massive reorganization of the transcriptome and respiratory metabolism.

Cokorinos E.C., Delmore J., Reyes A.R., Albuquerque B., Kjøbsted R., Jørgensen N.O., Tran J., Jatkar A., Cialdea K., Esquejo R.M., Meissen J., Calabrese M.F., Cordes J., Moccia R., Tess D., et. al.

The AMP-activated protein kinase (AMPK) is a potential therapeutic target for metabolic diseases based on its reported actions in the liver and skeletal muscle. We evaluated two distinct direct activators of AMPK: a non-selective activator of all AMPK complexes, PF-739, and an activator selective for AMPK β1-containing complexes, PF-249. In cells and animals, both compounds were effective at activating AMPK in hepatocytes, but only PF-739 was capable of activating AMPK in skeletal muscle. In diabetic mice, PF-739, but not PF-249, caused a rapid lowering of plasma glucose levels that was diminished in the absence of skeletal muscle, but not liver, AMPK heterotrimers and was the result of an increase in systemic glucose disposal with no impact on hepatic glucose production. Studies of PF-739 in cynomolgus monkeys confirmed translation of the glucose lowering and established activation of AMPK in skeletal muscle as a potential therapeutic approach to treat diabetic patients.

Morgunova G.V., Klebanov A.A., Marotta F., Khokhlov A.N.

There is an opinion that the chronological aging (ChA) of yeast and the stationary phase aging (SPA) of cultured animal and human cells are a consequence of growth medium acidification. However, a number of recent publications indicate that, although this process has a certain influence on the rate of “aging” of cells in the stationary growth phase, it does not determine it completely. Apparently, the key factor in this case is the restriction of cell proliferation, which leads to cell “aging” even under physiologically optimal conditions. During yeast ChA and mammalian cell SPA, the medium is getting acidified to pH ≤ 4. Prevention of acidification can prolong the culture life span, but the cells will still die, although at a slower rate. Effects of medium acidification during ChA and SPA can be explained by activation of highly conserved growth signaling pathways leading to oxidative stress, and these processes, in turn, can play a role in aging of multicellular organisms and development of age-related diseases. Our previous experiments on the effect of buffer capacity of growth medium on SPA of transformed Chinese hamster cells showed that 20 mM HEPES had no effect on cell growth rate; in addition, the growth curves of experimental and control cells reached a plateau on the same day. However, the cell saturation density in the medium with HEPES was lower (i.e., the cells were “older” in terms of the gerontological cell kinetics model); on the other hand, the rate of SPA was markedly reduced, compared to the control, although the cells were still “getting older.” It can be assumed that extracellular pH (by the way, well correlated with intracellular pH) is an important factor (I.A. Arshavsky’s concept of the role of acidic alteration in aging) but not the key factor determining the survival of cells in a stationary culture.

Howell J.J., Hellberg K., Turner M., Talbott G., Kolar M.J., Ross D.S., Hoxhaj G., Saghatelian A., Shaw R.J., Manning B.D.

Metformin is the most widely prescribed drug for the treatment of type 2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.

Zhang C., Li M., Ma T., Zong Y., Cui J., Feng J., Wu Y., Lin S., Lin S.

Morgunova G.V., Klebanov A.A., Khokhlov A.N.

In the review, the main types of autophagy (macroautophagy, microautophagy, and chaperonemediated autophagy) are shortly described. Data about the character of the influence of autophagy on the aging process and on the development of some neurodegenerative diseases in various organisms are analyzed. It is noted that this effect is usually (though not always) beneficial. Results of investigations of the phenomenon in experiments on mice, nematodes, fruit flies, bacteria, yeast, and cell cultures of higher organisms are considered. Obvious relationship between autophagy activation and cell proliferation restriction is emphasized. The latter, in our opinion, is the main cause of age-related accumulation of various defects (the most important of them is DNA damage) in cells and tissues, which leads to an increase in the death probability (i.e., to aging). It is concluded that studies of the role of autophagy in the aging process on the models of chronological aging in yeast or stationary phase aging of cell cultures could be considered as the most appropriate approach to the problem solution.

Jeon S.

5′-adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that was originally identified as the key player in maintaining cellular energy homeostasis. Intensive research over the last decade has identified diverse molecular mechanisms and physiological conditions that regulate the AMPK activity. AMPK regulates diverse metabolic and physiological processes and is dysregulated in major chronic diseases, such as obesity, inflammation, diabetes and cancer. On the basis of its critical roles in physiology and pathology, AMPK is emerging as one of the most promising targets for both the prevention and treatment of these diseases. In this review, we discuss the current understanding of the molecular and physiological regulation of AMPK and its metabolic and physiological functions. In addition, we discuss the mechanisms underlying the versatile roles of AMPK in diabetes and cancer.

Yavari A., Stocker C., Ghaffari S., Wargent E., Steeples V., Czibik G., Pinter K., Bellahcene M., Woods A., Martínez de Morentin P., Cansell C., Lam B.H., Chuster A., Petkevicius K., Nguyen-Tu M., et. al.

Morgunova G.V., Klebanov A.A., Khokhlov A.N.

Problems related to the interpretation of data obtained during testing of potential geroprotectors in cytogerontological experiments are considered. It is emphasized that such compounds/physical factors should influence the processes leading to the age-related increase of death probability of multicellular organisms (primarily human, in whose aging gerontologists are mainly interested). However, in the authors’ opinion, compounds that can be used to treat age-related diseases can hardly be classified as geroprotectors. It is noted that, in the model systems using cultured cells, researchers usually evaluate their viability, the criteria of which strongly depend on the aging theory that is shared by the experimenters. In addition, it is very important what cells are used in the studies—normal or transformed cells of multicellular organisms, unicellular eukaryotic or prokaryotic organisms, etc. In particular, the biologically active compounds that decrease the viability of cultured cancer cells, similarly to the compounds that increase the viability of normal cultured cells, may increase the life span of experimental animals and humans. Various problems with interpretation of data obtained with the Hayflick model, the stationary phase aging model, and the cell kinetics model, as well as in experiments on evaluation of cell colony-forming efficiency, are analyzed. The approaches discussed are illustrated on the example of the results of gerontological studies of rapamycin, a well-known mTOR inhibitor. It is assumed that factors retarding the stationary phase aging (chronological aging) of cultured cells are, apparently, the most promising geroprotectors, although the specific mechanisms of their action may vary considerably.

Khokhlov A.N.

Two model systems, “replicative aging” and “chronological aging” (CA), which are used for gerontological research on the yeast Saccharomyces cerevisiae, are compared. In the first case, the number of daughter cells generated by an individual mother cell before cell propagation irreversibly stops is analyzed. This makes the model very similar to the well-known Hayflick model. In the case of CA, the survival of yeast cell population in the stationary phase of growth is studied. It is noted that the second model is similar to the “stationary phase aging” model, which is used in the author’s laboratory for cytogerontological studies on animal and human cells. It is assumed that the concept of cell proliferation restriction as the main cause of age-related accumulation in the cells of multicellular organisms of macromolecular defects (primarily DNA damage) leading to deterioration of tissue and organ functioning and, as a result, to an increase in the death probability allows explaining how the aging process proceeds in almost any living organisms. Apparently, in all cases, this process is initiated by the appearance of slow propagating (or not propagating at all) cells, which leads to the termination of “dilution,” with the help of new cells, of macromolecular defects accumulating at the level of whole cell population. It is concluded that data on the geropromoter or geroprotector activity of various factors obtained in tests on the yeast CA model can be used with a high reliability to understand the mechanisms of human aging and longevity.

Na H., Park J., Pyo J., Jeon H., Kim Y., Arking R., Yoo M.

We delineated the mechanism regulating the inhibition of centrosome amplification by metformin in Drosophila intestinal stem cells (ISCs). Age-related changes in tissue-resident stem cells may be closely associated with tissue aging and age-related diseases, such as cancer. Centrosome amplification is a hallmark of cancers. Our recent work showed that Drosophila ISCs are an excellent model for stem cell studies evaluating age-related increase in centrosome amplification. Here, we showed that metformin, a recognized anti-cancer drug, inhibits age- and oxidative stress-induced centrosome amplification in ISCs. Furthermore, we revealed that this effect is mediated via down-regulation of AKT/target of rapamycin (TOR) activity, suggesting that metformin prevents centrosome amplification by inhibiting the TOR signaling pathway. Additionally, AKT/TOR signaling hyperactivation and metformin treatment indicated a strong correlation between DNA damage accumulation and centrosome amplification in ISCs, suggesting that DNA damage might mediate centrosome amplification. Our study reveals the beneficial and protective effects of metformin on centrosome amplification via AKT/TOR signaling modulation. We identified a new target for the inhibition of age- and oxidative stress-induced centrosome amplification. We propose that the Drosophila ISCs may be an excellent model system for in vivo studies evaluating the effects of anti-cancer drugs on tissue-resident stem cell aging.

Ulgherait M., Rana A., Rera M., Graniel J., Walker D.

AMPK exerts prolongevity effects in diverse species; however, the tissue-specific mechanisms involved are poorly understood. Here, we show that upregulation of AMPK in the adult Drosophila nervous system induces autophagy both in the brain and also in the intestinal epithelium. Induction of autophagy is linked to improved intestinal homeostasis during aging and extended lifespan. Neuronal upregulation of the autophagy-specific protein kinase Atg1 is both necessary and sufficient to induce these intertissue effects during aging and to prolong the lifespan. Furthermore, upregulation of AMPK in the adult intestine induces autophagy both cell autonomously and non-cell-autonomously in the brain, slows systemic aging, and prolongs the lifespan. We show that the organism-wide response to tissue-specific AMPK/Atg1 activation is linked to reduced insulin-like peptide levels in the brain and a systemic increase in 4E-BP expression. Together, these results reveal that localized activation of AMPK and/or Atg1 in key tissues can slow aging in a non-cell-autonomous manner.

Colman R.J., Beasley T.M., Kemnitz J.W., Johnson S.C., Weindruch R., Anderson R.M.

Caloric restriction (CR) without malnutrition increases longevity and delays the onset of age-associated disorders in short-lived species, from unicellular organisms to laboratory mice and rats. The value of CR as a tool to understand human ageing relies on translatability of CR’s effects in primates. Here we show that CR significantly improves age-related and all-cause survival in monkeys on a long-term ~30% restricted diet since young adulthood. These data contrast with observations in the 2012 NIA intramural study report, where a difference in survival was not detected between control-fed and CR monkeys. A comparison of body weight of control animals from both studies with each other, and against data collected in a multi-centred relational database of primate ageing, suggests that the NIA control monkeys were effectively undergoing CR. Our data indicate that the benefits of CR on ageing are conserved in primates.

Jinesh S., Özüpek B., Aditi P.

Driven by genetic and environmental factors, aging is a physiological process responsible for age-related degenerative changes in the body, cognitive decline, and impaired overall wellbeing. Notably, premature aging as well as the emergence of progeroid syndromes have posed concerns regarding chronic health conditions and comorbidities in the aging population. Accelerated telomere attrition is also implicated in metabolic dysfunction and the development of metabolic disorders. Impaired metabolic homeostasis arises secondary to age-related increases in the synthesis of free radicals, decreased oxidative capacity, impaired antioxidant defense, and disrupted energy metabolism. In particular, several cellular and molecular mechanisms of aging have been identified to decipher the influence of premature aging on metabolic diseases. These include defective DNA repair, telomere attrition, epigenetic alterations, and dysregulation of nutrient-sensing pathways. The role of telomere attrition premature aging in the pathogenesis of metabolic diseases has been largely attributed to pro-inflammatory states that promote telomere shortening, genetic mutations in the telomerase reverse transcriptase, epigenetic alteration, oxidative stress, and mitochondrial dysfunctions. Nonetheless, the therapeutic interventions focus on restoring the length of telomeres and may include treatment approaches to restore telomerase enzyme activity, promote alternative lengthening of telomeres, counter oxidative stress, and decrease the concentration of pro-inflammatory cytokines. Given the significance and robust potential of delaying telomere attrition in age-related metabolic diseases, this review aimed to explore the molecular and cellular mechanisms of aging underlying premature telomere attrition and metabolic diseases, assimilating evidence from both human and animal studies.

Li T., Huang N., Chen H., Yang Y., Zhang J., Xu W., Gong H., Gong C., Yang M., Zhao T., Wang F., Xiao H.

ABSTRACTTime‐restricted feeding (TRF) is a distinct regimen of intermittent fasting advocated for health improving. Although nighttime TRF (NRF) in rodents is analogous to daytime TRF (DRF) in humans and has health benefits, the effects of DRF on rodent's health remain uncertain. The adverse health effects of DRF in rodents are primarily attributed to its implementation‐induced temporal shift in the expression of circadian rhythm‐related genes. However, studies also demonstrate the health–beneficial effect of restricted feeding itself on metabolic homeostasis, particularly in periphery tissues. Moreover, the direct effects of DRF on aging progression in rodents are underexplored, highlighting a gap in current research. To explore the overall health effects of long‐term DRF in rodents, especially its influence on aging progression, we investigated the impact of long‐term DRF on mice under a progeric aging condition. Results showed that both 4‐h and 8‐h DRF regimens exerted positive effects on aging retardation; these effects were manifested as improved physical and memory capacities, enhanced liver and kidney functions, and reduced oxidative damage and inflammatory response. These DRF regimens also lowered the manifestation of aging‐related markers in peripheral tissues, with decreased SA‐β‐gal staining and p16 expression. Mechanistically, DRF regimens, especially DRF8, upregulated AMPK signaling and downregulated mTORC1 signaling. Interestingly, the health benefits of DRF are similar to those of metformin intervention. In conclusion, our study demonstrates for the first time that DRF effectively counteracts oxidative stress‐induced aging progression in mice, supporting the viewpoint that TRF as a promising strategy for preventing aging and aging‐related disorders.

Russo L., Babboni S., Andreassi M.G., Daher J., Canale P., Del Turco S., Basta G.

Cellular senescence is a state of permanent cell cycle arrest accompanied by metabolic activity and characteristic phenotypic changes. This process is crucial for developing age-related diseases, where excessive calorie intake accelerates metabolic dysfunction and aging. Overnutrition disturbs key metabolic pathways, including insulin/insulin-like growth factor signaling (IIS), the mammalian target of rapamycin (mTOR), and AMP-activated protein kinase. The dysregulation of these pathways contributes to insulin resistance, impaired autophagy, exacerbated oxidative stress, and mitochondrial dysfunction, further enhancing cellular senescence and systemic metabolic derangements. On the other hand, dysfunctional endothelial cells and adipocytes contribute to systemic inflammation, reduced nitric oxide production, and altered lipid metabolism. Numerous factors, including extracellular vesicles, mediate pathological communication between the vascular system and adipose tissue, amplifying metabolic imbalances. Meanwhile, caloric restriction (CR) emerges as a potent intervention to counteract overnutrition effects, improve mitochondrial function, reduce oxidative stress, and restore metabolic balance. CR modulates pathways such as IIS, mTOR, and sirtuins, enhancing glucose and lipid metabolism, reducing inflammation, and promoting autophagy. CR can extend the health span and mitigate age-related diseases by delaying cellular senescence and improving healthy endothelial–adipocyte interactions. This review highlights the crosstalk between endothelial cells and adipocytes, emphasizing CR potential in counteracting overnutrition-induced senescence and restoring vascular homeostasis.

Shilovsky G.A.

Numerous regulatory cascades link the cell response to oxidative stress and the mechanisms that maintain homeostasis and cell viability. The review summarizes the molecular mechanisms of interaction of the autophagy protein p62 with cell defense systems, primarily through the NRF2/KEAP1/ARE pathway. Understanding the cross-regulation of antioxidant defense and autophagy pathways contributes to the search for promising molecular targets to prevent and treat age-related diseases.

Shilovsky G.A., Sorokina E.V., Akhayev D.N.

Mitochondria are an important source of reactive oxygen species in skeletal muscle. Mitochondrial dysfunction accompanies the development of age-related human diseases. Increased production of reactive oxygen species contributes to muscle atrophy caused, for example, by physical inactivity. Many regulatory pathways involved in mitochondrial biogenesis are targets of anti-aging therapies. Active lifestyle and exercise prevent age-related damage to skeletal muscle mitochondria. Another way to correct the action of reactive oxygen species is the use of antioxidants directly targeted to the mitochondria. Treatment with mitochondria-targeted antioxidants attenuates mitochondrial degeneration, improves age-related skeletal muscle function, and protects muscles from atrophy. This review presents data on the use of mitochondrial-directed antioxidants and exercise to maintain the structural and functional state of mitochondria, and protect muscles from sarcopenia.

Wang D., Chen K., Wang Z., Wu H., Li Y.

AbstractSince the 12 major signs of aging were revealed in 2023, people's interpretation of aging will go further, which is of great significance for understanding the occurrence, development, and intervention in the aging process. As one of the 12 major signs of aging, cellular senescence refers to the process in which the proliferation and differentiation ability of cells decrease under stress stimulation or over time, often manifested as changes in cell morphology, cell cycle arrest, and decreased metabolic function. Interferon (IFN), as a secreted ligand for specific cell surface receptors, can trigger the transcription of interferon‐stimulated genes (ISGs) and play an important role in cellular senescence. In addition, IFN serves as an important component of SASP, and the activation of the IFN signaling pathway has been shown to contribute to cell apoptosis and senescence. It is expected to delay cellular senescence by linking IFN with cellular senescence and studying the effects of IFN on cellular senescence and its mechanism. This article provides a review of the research on the relationship between IFN and cellular senescence by consulting relevant literature.

Shilovsky G.A., Sorokina E.V., Akhaev D.N.

Mitochondria are an important source of reactive oxygen species in skeletal muscles. Mitochondrial dysfunction accompanies the development of age-related human diseases. An increased production of reactive oxygen species contributes to the muscle atrophy caused, for example, by the absence of physical activity. Many regulatory pathways involved in the mitochondrial biogenesis are targets of anti-aging therapy. An active lifestyle and physical exercise prevent age-related damage to mitochondria in skeletal muscles. The use of antioxidants aimed directly at mitochondria is another way to correct the effect of reactive oxygen species. The treatment with mitochondria-targeted antioxidants weakens the mitochondrial degeneration, improves the age-related function of skeletal muscles, and protects the muscles from atrophy. Data are presented on the use of mitochondria-targeted antioxidants and physical exercises to maintain the structural and functional state of mitochondria and on the protection of muscles from sarcopenia.

Park S.C., Lee Y., Cho K.A., Kim S.Y., Lee Y., Lee S., Lim I.K.

Biological responsiveness refers to the capacity of living organisms to adapt to changes in both their internal and external environments through physiological and behavioral mechanisms. One of the prominent aspects of aging is the decline in this responsiveness, which can lead to a deterioration in the processes required for maintenance, survival, and growth. The vital link between physiological responsiveness and the essential life processes lies within the signaling systems. To devise effective strategies for controlling the aging process, a comprehensive reevaluation of this connecting loop is imperative. This review aims to explore the impact of aging on signaling systems responsible for responsiveness and introduce a novel perspective on intervening in the aging process by restoring the compromised responsiveness. These innovative mechanistic approaches for modulating altered responsiveness hold the potential to illuminate the development of action plans aimed at controlling the aging process and treating age-related disorders.

Morgunova G.V., Shilovsky G.A., Khokhlov A.N.

Circadian rhythms ensure the synchronization of the physiology of cells and tissues in accordance with daily changes in the environment. These rhythms are maintained by transcriptional oscillators located in various organism cells. One of the rhythm sensors for the circadian clock is the intake of nutrients, this synchronizer is especially important in peripheral tissues. With age, the work of both the central and peripheral clock is disturbed. In old age, the amplitude of rhythms decreases and the peaks of expression of clock genes shift. Such changes affect not only the circadian, but also other rhythms. Promising ways to maintain circadian rhythms are a variety of dietary patterns, including both calorie restriction, well known for its ability to prolong the lifespan of laboratory animals, and time-restricted feeding. It is now known that intracellular metabolic sensors are also involved in regulation of the circadian clock. Among these sensors, it should be especially noted AMPK, which coordinates many catabolic and anabolic processes and participates in the implementation of the effect of calorie restriction. It is assumed that non-drug modulation of AMPK activity will not only help fight metabolic disorders, but also maintain circadian rhythms. The review considers the role of AMPK and some other metabolic sensors in the regulation of the circadian clock.

Kaur L., Neelam, Hajam Y.A., Kumar R., Reshi M.S., Rai S.

Diabetes is an endocrinometabolic disorder caused due to the irregular glucose metabolism. Insulin is secreted by pancreatic islets of β-cells. Hence, the pancreas is known as a “glucose regulator” that facilitates in regulating the synthesis and secretion of insulin which in turn facilitates in keeping blood glucose in balance. The complications  related to diabetes range from hyperglycemia, metabolic dysfunction, reproductive abnormalities, neuronal and renal damage. Various drugs and remedies are available for the treatment of diabetes coming from allopathy, homeopathy and ayurveda and are available since the past few decades. Moreover, in current era, nanomedicines prepared from various different plant parts and other polymeric compounds are are under consideration for the treatment of polygenic disease and associated complications. However, they are also having some demerits. Therefore, chitosanChitosan based nanopolymeric might be a better option for the treatment of diabetes and associated complication. In this chapter chitosanChitosan based nanoformualtions has been discussed along with their role in treating of diabetes.

Yang L.

In the long run of human history, a key responsibility has been the fight for food. Food is not always abundant, and the human body has to adjust by regulating nutrient-sensing signals to varying food availability. During the fed state, extra nutrients are stored in the body for further use. During the fasting state, the human body needs to adjust its metabolism to fight against low nutrient supply. Upon aging, the body has a decreased need for food intake and digestion and absorption are reduced, resulting in a state of unbalanced supply of various nutrients. This activates or inactivates corresponding nutrient sensing signals to adjust to the aging process. In this chapter, we discuss major nutrient sensing signals during aging, including the AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), sirtuin (SIRT), and insulin-like growth factor 1 (IGF-1) pathways. We also discuss the effects of calorie restriction on aging and the relative nutrient sensing signaling pathways.

Sikora E.

Aging is the driver for aging-related disorders, as the molecular mechanisms responsible for aging and various disease conditions are the same. Thus modifying these molecular processes may alleviate the hallmarks of aging and therefore prolong healthspan. This chapter discusses how diet may affect the insulin/insulin-like growth factor 1, 5′AMP-activated protein kinase, mechanistic target of rapamycin, and sirtuin signaling pathways. We also present some pharmacological approaches that influence these signaling pathways and the process of autophagy and cellular senescence. Pharmacological reduction in senescent cells in the organism or alleviation of their proinflammatory secretory phenotype by senolytics or senomorphics, respectively, provides hope for prolonging healthspan in the near future.

Shilovsky G.A., Ashapkin V.V.

Meshchaninov V.N., Tsyvian P.B., Myakotnykh V.S., Kovtun O.P., Shcherbakov D.L., Blagodareva M.S.

This article examines the phenomenon of “intrauterine programming,” which largely determines the further life cycle and the likelihood of developing a number of age-associated pathological processes. The possibility of the formation of pathological (accelerated) aging at various stages of ontogenesis is discussed with the use of a large amount of published material from the standpoint of modern science. The reasons, mechanisms and phenotypic manifestations of accelerated aging and the possibilities of the earliest, its diagnosis starting from the perinatal period, and prediction of age-associated pathologies are discussed in close interrelation.

Hassani B., Goshtasbi G., Nooraddini S., Firouzabadi N.

Biological aging or senescence is a course in which cellular function decreases over a period of time and is a consequence of altered signaling mechanisms that are triggered in stressed cells leading to cell damage. Aging is among the principal risk factors for many chronic illnesses such as cancer, cardiovascular disorders, and neurodegenerative diseases. Taking this into account, targeting fundamental aging mechanisms therapeutically may effectively impact numerous chronic illnesses. Selecting ideal therapeutic options in order to hinder the process of aging and decelerate the progression of age-related diseases is valuable. Along therapeutic options, life style modifications may well render the process of aging. The process of aging is affected by alteration in many cellular and signaling pathways amid which mTOR, SIRT1, and AMPK pathways are the most emphasized. Herein, we have discussed the mechanisms of aging focusing mainly on the mentioned pathways as well as the role of inflammation and autophagy in aging. Moreover, drugs and natural products with antiaging properties are discussed in detail.