bims-longev Biomed News
on Longevity
Issue of 2023–02–05
sixteen papers selected by
Andreea Nitescu
  1. Planetary Metronome as a Regulator of Lifespan and Aging Rate: The Metronomic Hypothesis.
  2. Mammal Aging is Controlled by an Evolvability-Based Adaptive Program.
  3. Caloric restriction induced epigenetic effects on aging.
  4. Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.
  5. Does Nrf2 Play a Role of a Master Regulator of Mammalian Aging?
  6. Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease.
  7. Inflammaging as a target for healthy ageing.
  8. Evolution of Longevity as a Species-Specific Trait in Mammals.
  9. Τhe Endless Beauty of Metformin: Does It Also Protect from Skin Aging? A Narrative Review.
  10. Editorial: Hypoxia as a therapeutic tool in search of healthy aging.
  11. Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice.
  12. Metabolism and exercise: the skeletal muscle clock takes centre stage.
  13. Nutrition and epigenetic programming.
  14. Effects of Qi-Fu-Yin on aging of APP/PS1 transgenic mice by regulating the intestinal microbiome.
  15. A dual MTOR/NAD+ acting gerotherapy.
  16. Transcription Factor Nrf2 and Mitochondria - Friends or Foes in the Regulation of Aging Rate.
  1. Biochemistry (Mosc). 2022 Dec;87(12): 1640-1650
    Planetary Metronome as a Regulator of Lifespan and Aging Rate: The Metronomic Hypothesis.
    Alexey M Olovnikov.
      A metronomic mechanism for the duration control of ontogenetic cycle periods of an animal is proposed. The components of the proposed metronomic system include the ventricular system of the brain, planet Earth as a generator of metronomic signals, and temporal DNA (tDNA) as a substrate that is epigenetically marked to measure elapsed time of ontogenesis. The metronomic system generates repetitive signals in the form of hydrodynamic disturbances in the cerebrospinal fluid (CSF). The metronomic effect arises due to the superposition of two processes - the near-wall unidirectional flow of CSF and oscillations in the movement of the planet. Hydrodynamic impacts of the metronome are transformed into nerve impulses that initiate epigenetic modification of tDNA in neurons, changing the content of factors expressed by this DNA for innervated targets of the body. The duration of ontogenetic cycle periods, including duration of the adult life, depends on the rate of addition of epigenetic marks to tDNA. This rate depends mainly on the frequency of the metronomic signals used by each particular species. But epigenetic modifications can also be influenced by factors that modulate metabolism and the rate of chromatin modifications, such as a calorie-restricted diet.
    Keywords:  CSF-contacting neurons; Earth motions; aging; hypothalamus; nutations; ontogenesis; polar motion; theories of aging; ventricular system of the brain
    DOI:  https://doi.org/10.1134/S0006297922120197
  2. Biochemistry (Mosc). 2022 Dec;87(12): 1405-1412
    Mammal Aging is Controlled by an Evolvability-Based Adaptive Program.
    Theodore C Goldsmith.
      As recently as in 2002 gerontologists widely thought that an aging program that purposely caused aging in mammals was impossible and therefore scientifically ridiculous because it violated widely accepted concepts regarding the nature of the evolution process. However, a number of modern evolutionary mechanics concepts such as group selection and evolvability suggest that an individually adverse trait like aging can evolve if it creates an advantage (reduced probability of extinction) for a population. Genetics discoveries suggest that aging creates multiple population advantages and, therefore, aging programs that purposely cause and regulate aging evolved in mammals. This led to various concepts regarding the nature of the program. One such concept is that aging is a completely genetically specified function of age, essentially a biological clock. However, this article presents evidence and theoretical basis for the idea that the programmed aging function is controlled by an adaptive mechanism that can sense local or temporary conditions that affect the optimum aging function and adjust it to compensate for those conditions. This issue is important for medical research because the sensing mechanisms and associated signaling provide additional points at which intervention in the aging process and associated highly age-related diseases could be attempted.
    Keywords:  ageing; aging theories; anti-aging medicine; evolution; evolvability; programmed aging; senescence
    DOI:  https://doi.org/10.1134/S000629792212001X
  3. Front Cell Dev Biol. 2022 ;10 1079920
    Caloric restriction induced epigenetic effects on aging.
    Jingfang Zhai, William H Kongsberg, Yinbo Pan, Canhua Hao, Xiaojing Wang, Jie Sun.
      Aging is the subject of many studies, facilitating the discovery of many interventions. Epigenetic influences numerous life processes by regulating gene expression and also plays a crucial role in aging regulation. Increasing data suggests that dietary changes can alter epigenetic marks associated with aging. Caloric restriction (CR)is considered an intervention to regulate aging and prolong life span. At present, CR has made some progress by regulating signaling pathways associated with aging as well as the mechanism of action of intercellular signaling molecules against aging. In this review, we will focus on autophagy and epigenetic modifications to elaborate the molecular mechanisms by which CR delays aging by triggering autophagy, epigenetic modifications, and the interaction between the two in caloric restriction. In order to provide new ideas for the study of the mechanism of aging and delaying aging.
    Keywords:  aging; autophagy; caloric restriction; drugs; epigenetic
    DOI:  https://doi.org/10.3389/fcell.2022.1079920
  4. J Transl Med. 2023 Jan 30. 21(1): 60
    Impact of the gut microbiota and associated metabolites on cardiometabolic traits, chronic diseases and human longevity: a Mendelian randomization study.
    Eloi Gagnon, Patricia L Mitchell, Hasanga D Manikpurage, Erik Abner, Nele Taba, Tõnu Esko, Nooshin Ghodsian, Sébastien Thériault, Patrick Mathieu, Benoit J Arsenault.
      Features of the gut microbiota have been associated with several chronic diseases and longevity in preclinical models as well as in observational studies. Whether these relations underlie causal effects in humans remains to be established. We aimed to determine whether the gut microbiota influences cardiometabolic traits as well as the risk of chronic diseases and human longevity using a comprehensive 2-Sample Mendelian randomization approach. We included as exposures 10 gut-associated metabolites and pathways and 57 microbial taxa abundance. We included as outcomes nine cardiometabolic traits (fasting glucose, fasting insulin, systolic blood pressure, diastolic blood pressure, HDL cholesterol, LDL cholesterol, triglycerides, estimated glomerular filtration rate, body mass index [BMI]), eight chronic diseases previously linked with the gut microbiota in observational studies (Alzheimer's disease, depression, type 2 diabetes, non-alcoholic fatty liver disease, coronary artery disease (CAD), stroke, osteoporosis and chronic kidney disease), as well as parental lifespan and longevity. We found 7 associations with evidence of causality before and after sensitivity analyses, but not after multiple testing correction (1198 tests). Most effect sizes (4/7) were small. The two largest exposure-outcome effects were markedly attenuated towards the null upon inclusion of BMI or alcohol intake frequency in multivariable MR analyses. While finding robust genetic instruments for microbiota features is challenging hence potentially inflating type 2 errors, these results do not support a large causal impact of human gut microbita features on cardiometabolic traits, chronic diseases or longevity. These results also suggest that the previously documented associations between gut microbiota and human health outcomes may not always underly causal relations.
    DOI:  https://doi.org/10.1186/s12967-022-03799-5
  5. Biochemistry (Mosc). 2022 Dec;87(12): 1465-1476
    Does Nrf2 Play a Role of a Master Regulator of Mammalian Aging?
    Roman A Zinovkin, Natalia D Kondratenko, Ludmila A Zinovkina.
      For a long time Nrf2 transcription factor has been attracting attention of researchers investigating phenomenon of aging. Numerous studies have investigated effects of Nrf2 on aging and cell senescence. Nrf2 is often considered as a key player in aging processes, however this needs to be proven. It should be noted that most studies were carried out on invertebrate model organisms, such as nematodes and fruit flies, but not on mammals. This paper briefly presents main mechanisms of mammalian aging and role of inflammation and oxidative stress in this process. The mechanisms of Nrf2 activity regulation, its involvement in aging and development of the senescence-associated secretory phenotype (SASP) are also discussed. Main part of this review is devoted to critical analysis of available experimental data on the role of Nrf2 in mammalian aging.
    Keywords:  age-related changes; aging; aging theories; inflammation; oxidative stress; transcription factor Nrf2
    DOI:  https://doi.org/10.1134/S0006297922120045
  6. Autophagy. 2023 Feb 02.
    Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease.
    Julian M Carosi, Timothy J Sargeant.
      In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered the commentary necessary because use of rapamycin in people with AD is a very real prospect and we wanted to present a balanced view of the likely consequences of MTOR (mechanistic target of rapamycin kinase) inhibition in the AD brain. We concluded that use of rapamycin, an MTOR inhibitor that increases macroautophagy/autophagy, could hold promise for prevention of AD if used early enough. However, MTOR inhibition appeared ineffectual in resolving existing amyloid pathology in AD mouse models. In this View article, we update these observations with new studies that have used rapamycin in AD models and provide evidence both for and against its use in AD. We also discuss rapamycin in the light of new research that describes rapamycin-induced autophagic stress in the ageing brain and autophagic stress as the origin of the amyloid plaque itself. We conclude that rapamycin will have complex effects on the brain in AD. Further, we hypothesize that lysosomal degradative capacity in the brain will likely determine how effective or detrimental rapamycin will be as a treatment of AD.
    Keywords:  Alzheimer disease; autophagy; dementia; lysosome; rapamycin
    DOI:  https://doi.org/10.1080/15548627.2023.2175569
  7. Age Ageing. 2023 Feb 01. pii: afac328. [Epub ahead of print]52(2):
    Inflammaging as a target for healthy ageing.
    Ben Dugan, Jessica Conway, Niharika A Duggal.
      Life expectancy has been on the rise for the past few decades, but healthy life expectancy has not kept pace, leading to a global burden of age-associated disorders. Advancing age is accompanied by a chronic increase in basal systemic inflammation, termed inflammaging, contributing towards an increased risk of developing chronic diseases in old age. This article reviews the recent literature to formulate hypotheses regarding how age-associated inflammaging plays a crucial role in driving chronic diseases and ill health in older adults. Here, we discuss how non-pharmacological intervention strategies (diet, nutraceutical supplements, phytochemicals, physical activity, microbiome-based therapies) targeting inflammaging restore health in older adults. We also consider alternative existing pharmacological interventions (Caloric restriction mimetics, p38 mitogen-activated protein kinase inhibitors) and explore novel targets (senolytics) aimed at combating inflammaging and optimising the ageing process to increase healthy lifespan.
    Keywords:  ageing; inflammaging; inflammation; interventions; older people; review
    DOI:  https://doi.org/10.1093/ageing/afac328
  8. Biochemistry (Mosc). 2022 Dec;87(12): 1579-1599
    Evolution of Longevity as a Species-Specific Trait in Mammals.
    Gregory A Shilovsky, Tatyana S Putyatina, Alexander V Markov.
      From the evolutionary point of view, the priority problem for an individual is not longevity, but adaptation to the environment associated with the need for survival, food supply, and reproduction. We see two main vectors in the evolution of mammals. One is a short lifespan and numerous offspring ensuring reproductive success (r-strategy). The other one is development of valuable skills in order compete successfully (K-strategy). Species with the K-strategy should develop and enhance specific systems (anti-aging programs) aimed at increasing the reliability and adaptability, including lifespan. These systems are signaling cascades that provide cell repair and antioxidant defense. Hence, any arbitrarily selected long-living species should be characterized by manifestation to a different extent of the longevity-favoring traits (e.g., body size, brain development, sociality, activity of body repair and antioxidant defense systems, resistance to xenobiotics and tumor formation, presence of neotenic traits). Hereafter, we will call a set of such traits as the gerontological success of a species. Longevity is not equivalent to the evolutionary or reproductive success. This difference between these phenomena reaches its peak in mammals due to the development of endothermy and cephalization associated with the cerebral cortex expansion, which leads to the upregulated production of oxidative radicals by the mitochondria (and, consequently, accelerated aging), increase in the number of non-dividing differentiated cells, accumulation of the age-related damage in these cells, and development of neurodegenerative diseases. The article presents mathematical indicators used to assess the predisposition to longevity in different species (including the standard mortality rate and basal metabolic rate, as well as their derivatives). The properties of the evolution of mammals (including the differences between modern mammals and their ancestral forms) are also discussed.
    Keywords:  Nrf2; age-related disorders; aging; anti-aging programs; evolution; gerontological success; lifespan; longevity quotient; oxidative stress; phenoptosis
    DOI:  https://doi.org/10.1134/S0006297922120148
  9. Adv Ther. 2023 Jan 30.
    Τhe Endless Beauty of Metformin: Does It Also Protect from Skin Aging? A Narrative Review.
    Evanthia Gouveri, Nikolaos Papanas.
      Metformin has shown multiple effects beyond its widely known antidiabetic effect. Impressively, it has already been proposed as an anti-aging factor. However, the potentially protective role of metformin in skin aging, the most common manifestation of aging, is not well examined. Existing evidence based on experimental studies suggests a potential anti-aging effect on skin. Proposed molecular skin anti-aging mechanisms of metformin include mainly reduction of nuclear factor kappa B (NF-κB) (p65) activity. Moreover, metformin appears to inhibit ultraviolet B (UVB)-induced secretion of pro-inflammatory cytokines. Nonetheless, data is still limited, and so more studies are needed. Importantly, we need more studies conducted in humans to further examine this interesting potential. Until then, whether oral administration of metformin or local use of the agent could be used to delay skin aging remains to be answered.
    Keywords:  Anti-aging; Metformin; Photoaging; Skin aging
    DOI:  https://doi.org/10.1007/s12325-023-02434-z
  10. Front Physiol. 2022 ;13 1112129
    Editorial: Hypoxia as a therapeutic tool in search of healthy aging.
    Alba Camacho-Cardenosa, Johannes Burtscher, Martin Burtscher, Marta Camacho-Cardenosa.
      
    Keywords:  aging; exercise; frail elderly; hypoxia; oxygen homeostasis
    DOI:  https://doi.org/10.3389/fphys.2022.1112129
  11. Front Aging Neurosci. 2022 ;14 1030807
    Identification and evaluation of midbrain specific longevity-related genes in exceptionally long-lived but healthy mice.
    Hyojung Kim, Yu-Jin Huh, Ji Hun Kim, Minkyung Jo, Joo-Heon Shin, Sang Chul Park, Jee-Yin Ahn, Yun-Il Lee, Yunjong Lee.
      Brain aging is a complex biological process that is affected by both genetic background and environment. The transcriptomic analysis of aged human and rodent brains has been applied to identify age-associated molecular and cellular processes for which intervention could possibly restore declining brain functions induced by aging. However, whether these age-associated genetic alterations are indeed involved in the healthy aging of the brain remains unclear. We herein characterized a naturally occurring, extremely long-lived (34 months of age) but healthy mouse group retaining well-preserved motor functions. Strikingly, these long-lived mice maintained tyrosine hydroxylase expression and dopaminergic fiber densities, even in the presence of persistent neuroinflammation and expression of aging markers. Combined with Endeavor gene prioritization, we identified the following midbrain-specific longevity-associated genes in the midbrain of these mice: aimp2, hexb, cacybp, akt2, nrf1, axin1, wwp2, sp2, dnajb9, notch, traf7, and lrp1. A detailed biochemical analysis of the midbrain of these long-lived mice confirmed the increased expression of Nrf1 and the activation of Akt1 and 2. Interestingly, dopaminergic neuroprotective and age-associated E3 ubiquitin ligase parkin expression was retained at high levels in the aforementioned midbrains, possibly supporting the suppression of its toxic substrates AIMP2 and PARIS. In contrast, the 24-month-old mice with dopaminergic neurite deficits failed to maintain parkin expression in the midbrain. AIMP2-induced cytotoxicity, mitochondrial stress, and neurite toxicity can be prevented by overexpression of parkin, Akt1, and Nrf1 in SH-SY5Y and PC12 cells, and basal expression of parkin, Akt1, and Nrf1 is required for maintenance of mitochondrial function and neurite integrity in PC12 cells. Taken together, this longevity-associated pathway could be a potential target of intervention to maintain nigrostriatal dopaminergic fibers and motor ability to ensure healthy longevity.
    Keywords:  AIMP2; Akt; NRF1; dopaminergic neurites; gene prioritization; longevity; motor function; parkin
    DOI:  https://doi.org/10.3389/fnagi.2022.1030807
  12. Nat Rev Endocrinol. 2023 Feb 01.
    Metabolism and exercise: the skeletal muscle clock takes centre stage.
    Ryan A Martin, Mark R Viggars, Karyn A Esser.
      Circadian rhythms that influence mammalian homeostasis and overall health have received increasing interest over the past two decades. The molecular clock, which is present in almost every cell, drives circadian rhythms while being a cornerstone of physiological outcomes. The skeletal muscle clock has emerged as a primary contributor to metabolic health, as the coordinated expression of the core clock factors BMAL1 and CLOCK with the muscle-specific transcription factor MYOD1 facilitates the circadian and metabolic programme that supports skeletal muscle physiology. The phase of the skeletal muscle clock is sensitive to the time of exercise, which provides a rationale for exploring the interactions between the skeletal muscle clock, exercise and metabolic health. Here, we review the underlying mechanisms of the skeletal muscle clock that drive muscle physiology, with a particular focus on metabolic health. Additionally, we highlight the interaction between exercise and the skeletal muscle clock as a means of reinforcing metabolic health and discuss the possible implications of the time of exercise as a chronotherapeutic approach.
    DOI:  https://doi.org/10.1038/s41574-023-00805-8
  13. Curr Opin Clin Nutr Metab Care. 2022 Dec 26.
    Nutrition and epigenetic programming.
    Carsten Carlberg, Eunike Velleuer.
       PURPOSE OF REVIEW: The aim of this study is to highlight the epigenomic programming properties of nutritional molecules and their metabolites in human tissues and cell types.
    RECENT FINDINGS: Chromatin is the physical expression of the epigenome and has a memory function on the level of DNA methylation, histone modification and 3-dimensional (3D) organization. This epigenetic memory does not only affect transient gene expression but also represents long-lasting decisions on cellular fate. The memory is based on an epigenetic programming process, which is directed by extracellular and intracellular signals that are sensed by transcription factors and chromatin modifiers. Many dietary molecules and their intermediary metabolites serve as such signals, that is they contribute to epigenetic programming and memory. In this context, we will discuss about molecules of intermediary energy metabolism affecting chromatin modifier actions, nutrition-triggered epigenetic memory in pre- and postnatal phases of life; and epigenetic programming of immune cells by vitamin D. These mechanisms explain some of the susceptibility for complex diseases, such as the metabolic syndrome, cancer and immune disorders.
    SUMMARY: The observation that nutritional molecules are able to modulate the epigenome initiated the new nutrigenomic subdiscipline nutritional epigenetics. The concept that epigenetic memory and programming is directed by our diet has numerous implications for the interpretation of disease risk including their prevention.
    DOI:  https://doi.org/10.1097/MCO.0000000000000900
  14. Front Cell Infect Microbiol. 2022 ;12 1048513
    Effects of Qi-Fu-Yin on aging of APP/PS1 transgenic mice by regulating the intestinal microbiome.
    Qiu-Yue Xiao, Tian-Yuan Ye, Xiao-Long Wang, Dong-Mei Qi, Xiao-Rui Cheng.
       Introduction: Alzheimer's disease is the most common form of dementia and closely related to aging. Qi-Fu-Yin is widely used to treat dementia, but its anti-aging effects is unknown.
    Methods: We used 11-month-old APP/PS1 transgenic mice for behavioral tests to observe the changes in cognitive function and age-related symptoms after Qi-Fu-Yin treatment. Fecal samples were collected for 16sRNA sequencing and metagenomic sequencing. Differences among the groups of intestinal microbiota and the associations with aging and intestinal microbiota were analyzed based on the results.
    Results: Here we found that Qi-Fu-Yin improved the ability of motor coordination, raised survival rate and prolonged the survival days under cold stress stimulation in aged APP/ PS1 transgenic mice. Our data from 16sRNA and metagenomic sequencing showed that at the Family level, the intestinal microbiota was significantly different among wild-type mice, APP/PS1 transgenic mice and the Qi-Fu-Yin group by PCA analysis. Importantly, Qi-Fu-Yin improved the functional diversity of the major KEGG pathways, carbohydrate-active enzymes, and major virulence factors in the intestinal flora of APP/PS1 transgenic mice. Among them, the functions of eight carbohydrate-active enzymes (GT2_Glycos_transf_2, GT4, GT41, GH2, CE1, CE10, CE3, and GH24) and the functions of top three virulence factors (defensive virulence factors, offensive virulence factors and nonspecific virulence factors) were significantly and positively correlated with the level of grasping ability. We further indicated that the Qi-Fu-Yin significantly reduced the plasma levels of IL-6.
    Conclusion: Our results indicated that the effects of Qi-Fu-Yin anti-aging of APP/PS1 transgenic mice might be through the regulation of intestinal flora diversity, species richness and the function of major active enzymes.
    Keywords:  APP/PS1 transgenic mice; Alzheimer disease; Qi-Fu-Yin; aging; microbiome
    DOI:  https://doi.org/10.3389/fcimb.2022.1048513
  15. bioRxiv. 2023 Jan 19. pii: 2023.01.16.523975. [Epub ahead of print]
    A dual MTOR/NAD+ acting gerotherapy.
    Jinmei Li, Sandeep Kumar, Kirill Miachin, Nicholas L Bean, Ornella Halawi, Scott Lee, JiWoong Park, Tanya H Pierre, Jin-Hui Hor, Shi-Yan Ng, Kelvin J Wallace, Niklas Rindtorff, Timothy M Miller, Michael L Niehoff, Susan A Farr, Rolf F Kletzien, Jerry Colca, Steven P Tanis, Yana Chen, Kristine Griffett, Kyle S McCommis, Brian N Finck, Tim R Peterson.
      The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it’s largely unclear how they might talk to each other in aging. In genome-wide CRISPRa screening with a novel class of N-O-Methyl-propanamide-containing compounds we named BIOIO-1001, we identified lipid metabolism centering on SIRT3 as a point of intersection of the mTOR/insulin and NAD+ pathways. In vivo testing indicated that BIOIO-1001 reduced high fat, high sugar diet-induced metabolic derangements, inflammation, and fibrosis, each being characteristic of non-alcoholic steatohepatitis (NASH). An unbiased screen of patient datasets suggested a potential link between the anti-inflammatory and anti-fibrotic effects of BIOIO-1001 in NASH models to those in amyotrophic lateral sclerosis (ALS). Directed experiments subsequently determined that BIOIO-1001 was protective in both sporadic and familial ALS models. Both NASH and ALS have no treatments and suffer from a lack of convenient biomarkers to monitor therapeutic efficacy. A potential strength in considering BIOIO-1001 as a therapy is that the blood biomarker that it modulates, namely plasma triglycerides, can be conveniently used to screen patients for responders. More conceptually, to our knowledge BIOIO-1001 is a first therapy that fits the geroscience hypothesis by acting on multiple core aging pathways and that can alleviate multiple conditions after they have set in.
    Brief Summary: These studies characterize a novel gerotherapy, BIOIO-1001, that identifies lipid metabolism as an intersection of the mTOR and NAD+ pathways.
    DOI:  https://doi.org/10.1101/2023.01.16.523975
  16. Biochemistry (Mosc). 2022 Dec;87(12): 1477-1486
    Transcription Factor Nrf2 and Mitochondria - Friends or Foes in the Regulation of Aging Rate.
    Gregory A Shilovsky, Vasily V Ashapkin.
      At the first sight, the transcription factor Nrf2 as a master regulator of cellular antioxidant systems, and mitochondria as the main source of reactive oxygen species (ROS), should play the opposite roles in determining the pace of aging. However, since the causes of aging cannot be confined to the oxidative stress, the role of Nrf2 role cannot be limited to the regulation of antioxidant systems, and moreover, the role of mitochondria is not confined to the ROS production. In this review, we discussed only one aspect of this problem, namely, the molecular mechanisms of interaction between Nrf2 and mitochondria that influence the rate of aging and the lifespan. Experimental data accumulated so far show that the Nrf2 activity positively affects both the mitochondrial dynamics and mitochondrial quality control. Nrf2 influences the mitochondrial function through various mechanisms, e.g., regulation of nuclear genome-encoded mitochondrial proteins and changes in the balance of ROS or other metabolites that affect the functioning of mitochondria. In turn, multiple regulatory proteins functionally associated with the mitochondria affect the Nrf2 activity and even form mutual regulatory loops with Nrf2. We believe that these loops enable the fine-tuning of the cellular redox balance and, possibly, of the cellular metabolism as a whole. It has been commonly accepted for a long time that all mitochondrial regulatory signals are mediated by the nuclear genome-encoded proteins, whereas the mitochondrial genome encodes only a few respiratory chain proteins and two ribosomal RNAs. Relatively recently, mtDNA-encoded signal peptides have been discovered. In this review, we discuss the data on their interactions with the nuclear regulatory systems, first of all, Nrf2, and their possible involvement in the regulation of the aging rate. The interactions between regulatory cascades that link the programs ensuring the maintenance of cellular homeostasis and cellular responses to the oxidative stress are a significant part of both aging and anti-aging programs. Therefore, understanding these interactions will be of great help in searching for the molecular targets to counteract aging-associated diseases and aging itself.
    Keywords:  Nrf2; aging; aging diseases; antioxidants; lifespan; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1134/S0006297922120057
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