1 6467 140 TISSUE-SPECIFIC EFFECTS OF EXERCISE AS NAD(+) -BOOSTING STRATEGY: CURRENT KNOWLEDGE AND FUTURE PERSPECTIVES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) ) IS AN EVOLUTIONARILY HIGHLY CONSERVED COENZYME WITH MULTI-FACETED CELL FUNCTIONS, INCLUDING ENERGY METABOLISM, MOLECULAR SIGNALING PROCESSES, EPIGENETIC REGULATION, AND DNA REPAIR. SINCE THE DISCOVERY THAT LOWER NAD(+) LEVELS ARE A SHARED CHARACTERISTIC OF VARIOUS DISEASES AND AGING PER SE, SEVERAL NAD(+) -BOOSTING STRATEGIES HAVE EMERGED. OTHER THAN PHARMACOLOGICAL AND NUTRITIONAL APPROACHES, EXERCISE IS THOUGHT TO RESTORE NAD(+) HOMEOSTASIS THROUGH METABOLIC ADAPTION TO CHRONICALLY RECURRING STATES OF INCREASED ENERGY DEMAND. IN THIS REVIEW WE DISCUSS THE IMPACT OF ACUTE EXERCISE AND EXERCISE TRAINING ON TISSUE-SPECIFIC NAD(+) METABOLISM OF RODENTS AND HUMANS TO HIGHLIGHT THE POTENTIAL VALUE AS NAD(+) -BOOSTING STRATEGY. BY INTERCONNECTING RESULTS FROM DIFFERENT INVESTIGATIONS, WE AIM TO DRAW ATTENTION TO TISSUE-SPECIFIC ALTERATIONS IN NAD(+) METABOLISM AND THE ASSOCIATED IMPLICATIONS FOR WHOLE-BODY NAD(+) HOMEOSTASIS. ACUTE EXERCISE LED TO PROFOUND ALTERATIONS OF INTRACELLULAR NAD(+) METABOLISM IN VARIOUS INVESTIGATIONS, WITH THE MAGNITUDE AND DIRECTION OF CHANGES BEING STRONGLY DEPENDENT ON THE APPLIED EXERCISE MODALITY, CELL TYPE, AND INVESTIGATED ANIMAL MODEL OR HUMAN POPULATION. EXERCISE TRAINING ELEVATED NAD(+) LEVELS AND NAD(+) METABOLISM ENZYMES IN VARIOUS TISSUES. BASED ON THESE RESULTS, WE DISCUSS MOLECULAR MECHANISMS THAT MIGHT CONNECT ACUTE EXERCISE-INDUCED DISRUPTIONS OF NAD(+) /NADH HOMEOSTASIS TO CHRONIC EXERCISE ADAPTIONS IN NAD(+) METABOLISM. TAKING THIS HYPOTHESIS-DRIVEN APPROACH, WE HOPE TO INSPIRE FUTURE RESEARCH ON THE MOLECULAR MECHANISMS OF EXERCISE AS NAD(+) -MODIFYING LIFESTYLE INTERVENTION, THEREBY ELUCIDATING THE POTENTIAL THERAPEUTIC VALUE IN NAD(+) -RELATED PATHOLOGIES. 2023 2 4585 48 NAD(+) AND VASCULAR DYSFUNCTION: FROM MECHANISMS TO THERAPEUTIC OPPORTUNITIES. NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) IS AN ESSENTIAL AND PLEIOTROPIC COENZYME INVOLVED NOT ONLY IN CELLULAR ENERGY METABOLISM, BUT ALSO IN CELL SIGNALING, EPIGENETIC REGULATION, AND POST-TRANSLATIONAL PROTEIN MODIFICATIONS. VASCULAR DISEASE RISK FACTORS ARE ASSOCIATED WITH ABERRANT NAD(+) METABOLISM. CONVERSELY, THE THERAPEUTIC INCREASE OF NAD(+) LEVELS THROUGH THE ADMINISTRATION OF NAD(+) PRECURSORS OR INHIBITORS OF NAD(+)-CONSUMING ENZYMES REDUCES CHRONIC LOW-GRADE INFLAMMATION, REACTIVATES AUTOPHAGY AND MITOCHONDRIAL BIOGENESIS, AND ENHANCES OXIDATIVE METABOLISM IN VASCULAR CELLS OF HUMANS AND RODENTS WITH VASCULAR PATHOLOGIES. AS SUCH, NAD(+) HAS EMERGED AS A POTENTIAL TARGET FOR COMBATTING AGE-RELATED CARDIOVASCULAR AND CEREBROVASCULAR DISORDERS. THIS REVIEW DISCUSSES NAD(+)-REGULATED MECHANISMS CRITICAL FOR VASCULAR HEALTH AND SUMMARIZES NEW ADVANCES IN NAD(+) RESEARCH DIRECTLY RELATED TO VASCULAR AGING AND DISEASE, INCLUDING HYPERTENSION, ATHEROSCLEROSIS, CORONARY ARTERY DISEASE, AND AORTIC ANEURYSMS. FINALLY, WE ENUMERATE CHALLENGES AND OPPORTUNITIES FOR NAD(+) REPLETION THERAPY WHILE ANTICIPATING THE FUTURE OF THIS EXCITING RESEARCH FIELD, WHICH WILL HAVE A MAJOR IMPACT ON VASCULAR MEDICINE. 2022 3 870 27 CHRONIC ALCOHOL BINGING INJURES THE LIVER AND OTHER ORGANS BY REDUCING NAD(+) LEVELS REQUIRED FOR SIRTUIN'S DEACETYLASE ACTIVITY. NAD(+) LEVELS ARE MARKEDLY REDUCED WHEN BLOOD ALCOHOL LEVELS ARE HIGH DURING BINGE DRINKING. THIS CAUSES LIVER INJURY TO OCCUR BECAUSE THE ENZYMES THAT REQUIRE NAD(+) AS A COFACTOR SUCH AS THE SIRTUIN DE-ACETYLASES CANNOT DE-ACETYLATE ACETYLATED PROTEINS SUCH AS ACETYLATED HISTONES. THIS PREVENTS THE EPIGENETIC CHANGES THAT REGULATE METABOLIC PROCESSES AND WHICH PREVENT ORGAN INJURY SUCH AS FATTY LIVER IN RESPONSE TO ALCOHOL ABUSE. HYPER ACETYLATION OF NUMEROUS REGULATORY PROTEINS DEVELOPS. SYSTEMIC MULTI-ORGAN INJURY OCCURS WHEN NAD(+) IS REDUCED. FOR INSTANCE THE CIRCADIAN CLOCK IS ALTERED IF NAD(+) IS NOT AVAILABLE. CELL CYCLE ARREST OCCURS DUE TO UP REGULATION OF CELL CYCLE INHIBITORS LEADING TO DNA DAMAGE, MUTATIONS, APOPTOSIS AND TUMORIGENESIS. NAD(+) IS LINKED TO AGING IN THE REGULATION OF TELOMERE STABILITY. NAD(+) IS REQUIRED FOR MITOCHONDRIAL RENEWAL. ALCOHOL DEHYDROGENASE IS PRESENT IN EVERY VISCERAL ORGAN IN THE BODY SO THAT THERE IS A SYSTEMIC REDUCTION OF NAD(+) LEVELS IN ALL OF THESE ORGANS DURING BINGE DRINKING. 2016 4 3115 48 GEROMETABOLITES: THE PSEUDOHYPOXIC AGING SIDE OF CANCER ONCOMETABOLITES. ONCOMETABOLITES ARE DEFINED AS SMALL-MOLECULE COMPONENTS (OR ENANTIOMERS) OF NORMAL METABOLISM WHOSE ACCUMULATION CAUSES SIGNALING DYSREGULATION TO ESTABLISH A MILIEU THAT INITIATES CARCINOGENESIS. IN A SIMILAR MANNER, WE PROPOSE THE TERM "GEROMETABOLITES" TO REFER TO SMALL-MOLECULE COMPONENTS OF NORMAL METABOLISM WHOSE DEPLETION CAUSES SIGNALING DYSREGULATION TO ESTABLISH A MILIEU THAT DRIVES AGING. IN AN INVESTIGATION OF THE PATHOGENIC ACTIVITIES OF THE CURRENTLY RECOGNIZED ONCOMETABOLITES R(-)-2-HYDROXYGLUTARATE (2-HG), FUMARATE, AND SUCCINATE, WHICH ACCUMULATE DUE TO MUTATIONS IN ISOCITRATE DEHYDROGENASES (IDH), FUMARATE HYDRATASE (FH), AND SUCCINATE DEHYDROGENASE (SDH), RESPECTIVELY, WE ILLUSTRATE THE FACT THAT METABOLIC PSEUDOHYPOXIA, THE ACCUMULATION OF HYPOXIA-INDUCIBLE FACTOR (HIFALPHA) UNDER NORMOXIC CONDITIONS, AND THE SUBSEQUENT WARBURG-LIKE REPROGRAMMING THAT SHIFTS GLUCOSE METABOLISM FROM THE OXIDATIVE PATHWAY TO AEROBIC GLYCOLYSIS ARE THE SAME MECHANISMS THROUGH WHICH THE DECLINE OF THE "GEROMETABOLITE" NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)(+) REVERSIBLY DISRUPTS NUCLEAR-MITOCHONDRIAL COMMUNICATION AND CONTRIBUTES TO THE DECLINE IN MITOCHONDRIAL FUNCTION WITH AGE. FROM AN EVOLUTIONARY PERSPECTIVE, IT IS REASONABLE TO VIEW NAD(+)-DRIVEN MITOCHONDRIAL HOMEOSTASIS AS A CONSERVED RESPONSE TO CHANGES IN ENERGY SUPPLIES AND OXYGEN LEVELS. SIMILARLY, THE NATURAL ABILITY OF 2-HG TO SIGNIFICANTLY ALTER EPIGENETICS MIGHT REFLECT AN EVOLUTIONARILY ANCIENT ROLE OF CERTAIN METABOLITES TO SIGNAL FOR ELEVATED GLUTAMINE/GLUTAMATE METABOLISM AND/OR OXYGEN DEFICIENCY. HOWEVER, WHEN CHRONICALLY ALTERED, THESE RESPONSES BECOME CONSERVED CAUSES OF AGING AND CANCER. BECAUSE HIFALPHA-DRIVEN PSEUDOHYPOXIA MIGHT DRIVE THE OVERPRODUCTION OF 2-HG, THE INTRIGUING POSSIBILITY EXISTS THAT THE DECLINE OF GEROMETABOLITES SUCH AS NAD(+) COULD PROMOTE THE CHRONIC ACCUMULATION OF ONCOMETABOLITES IN NORMAL CELLS DURING AGING. IF THE SOLE ACTIVATION OF A WARBURG-LIKE METABOLIC REPROGRAMMING IN NORMAL TISSUES MIGHT BE ABLE TO SIGNIFICANTLY INCREASE THE ENDOGENOUS PRODUCTION OF BONA FIDE ETIOLOGICAL DETERMINANTS IN CANCER, SUCH AS ONCOMETABOLITES, THIS UNDESIRABLE TRADE-OFF BETWEEN MITOCHONDRIAL DYSFUNCTION AND ACTIVATION OF ONCOMETABOLITES PRODUCTION MIGHT THEN PAVE THE WAY FOR THE EPIGENETIC INITIATION OF CARCINOGENESIS IN A STRICTLY METABOLIC-DEPENDENT MANNER. PERHAPS IT IS TIME TO DEFINITELY ADOPT THE VIEW THAT AGING AND AGING DISEASES INCLUDING CANCER ARE GOVERNED BY A PIVOTAL REGULATORY ROLE OF METABOLIC REPROGRAMMING IN CELL FATE DECISIONS. 2014 5 5720 31 SIRTUINS LINK INFLAMMATION AND METABOLISM. SIRTUINS (SIRT), FIRST DISCOVERED IN YEAST AS NAD+ DEPENDENT EPIGENETIC AND METABOLIC REGULATORS, HAVE COMPARABLE ACTIVITIES IN HUMAN PHYSIOLOGY AND DISEASE. MOUNTING EVIDENCE SUPPORTS THAT THE SEVEN-MEMBER MAMMALIAN SIRTUIN FAMILY (SIRT1-7) GUARD HOMEOSTASIS BY SENSING BIOENERGY NEEDS AND RESPONDING BY MAKING ALTERATIONS IN THE CELL NUTRIENTS. SIRTUINS PLAY A CRITICAL ROLE IN RESTORING HOMEOSTASIS DURING STRESS RESPONSES. INFLAMMATION IS DESIGNED TO "DEFEND AND MEND" AGAINST THE INVADING ORGANISMS. EMERGING EVIDENCE SUPPORTS THAT METABOLISM AND BIOENERGY REPROGRAMMING DIRECT THE SEQUENTIAL COURSE OF INFLAMMATION; FAILURE OF HOMEOSTASIS RETRIEVAL RESULTS IN MANY CHRONIC AND ACUTE INFLAMMATORY DISEASES. ANABOLIC GLYCOLYSIS QUICKLY INDUCED (COMPARED TO OXIDATIVE PHOSPHORYLATION) FOR ROS AND ATP GENERATION IS NEEDED FOR IMMUNE ACTIVATION TO "DEFEND" AGAINST INVADING MICROORGANISMS. LIPOLYSIS/FATTY ACID OXIDATION, ESSENTIAL FOR CELLULAR PROTECTION/HIBERNATION AND CELL SURVIVAL IN ORDER TO "MEND," LEADS TO IMMUNE REPRESSION. ACUTE/CHRONIC INFLAMMATIONS ARE LINKED TO ALTERED GLYCOLYSIS AND FATTY ACID OXIDATION, AT LEAST IN PART, BY NAD+ DEPENDENT FUNCTION OF SIRTUINS. THERAPEUTICALLY TARGETING SIRTUINS MAY PROVIDE A NEW CLASS OF INFLAMMATION AND IMMUNE REGULATORS. THIS REVIEW DISCUSSES HOW SIRTUINS INTEGRATE METABOLISM, BIOENERGETICS, AND IMMUNITY DURING INFLAMMATION AND HOW SIRTUIN-DIRECTED TREATMENT IMPROVES OUTCOME IN CHRONIC INFLAMMATORY DISEASES AND IN THE EXTREME STRESS RESPONSE OF SEPSIS. 2016 6 5719 34 SIRTUINS IN NEURODEGENERATIVE DISEASES: AN UPDATE ON POTENTIAL MECHANISMS. SILENT INFORMATION REGULATOR 2 PROTEINS (SIRTUINS OR SIRTS) ARE A GROUP OF DEACETYLASES (OR DEACYLASES) WHOSE ACTIVITIES ARE DEPENDENT ON AND REGULATED BY NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)). COMPELLING EVIDENCE SUPPORTS THAT SIRTUINS PLAY MAJOR ROLES IN MANY ASPECTS OF PHYSIOLOGY, ESPECIALLY IN PATHWAYS RELATED TO AGING - THE PREDOMINANT AND UNIFYING RISK FACTOR FOR NEURODEGENERATIVE DISEASES. IN THIS REVIEW, WE HIGHLIGHT THE MOLECULAR MECHANISMS UNDERLYING THE PROTECTIVE EFFECTS OF SIRTUINS IN NEURODEGENERATIVE DISEASES, FOCUSING ON PROTEIN HOMEOSTASIS, NEURAL PLASTICITY, MITOCHONDRIAL FUNCTION, AND SUSTAINED CHRONIC INFLAMMATION. WE WILL ALSO EXAMINE THE POTENTIAL AND CHALLENGES OF TARGETING SIRTUIN PATHWAYS TO BLOCK THESE PATHOGENIC PATHWAYS. 2013 7 313 31 ALCOHOL METABOLISM AND EPIGENETICS CHANGES. METABOLITES, INCLUDING THOSE GENERATED DURING ETHANOL METABOLISM, CAN IMPACT DISEASE STATES BY BINDING TO TRANSCRIPTION FACTORS AND/OR MODIFYING CHROMATIN STRUCTURE, THEREBY ALTERING GENE EXPRESSION PATTERNS. FOR EXAMPLE, THE ACTIVITIES OF ENZYMES INVOLVED IN EPIGENETIC MODIFICATIONS SUCH AS DNA AND HISTONE METHYLATION AND HISTONE ACETYLATION, ARE INFLUENCED BY THE LEVELS OF METABOLITES SUCH AS NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD), ADENOSINE TRIPHOSPHATE (ATP), AND S-ADENOSYLMETHIONINE (SAM). CHRONIC ALCOHOL CONSUMPTION LEADS TO SIGNIFICANT REDUCTIONS IN SAM LEVELS, THEREBY CONTRIBUTING TO DNA HYPOMETHYLATION. SIMILARLY, ETHANOL METABOLISM ALTERS THE RATIO OF NAD+ TO REDUCED NAD (NADH) AND PROMOTES THE FORMATION OF REACTIVE OXYGEN SPECIES AND ACETATE, ALL OF WHICH IMPACT EPIGENETIC REGULATORY MECHANISMS. IN ADDITION TO ALTERED CARBOHYDRATE METABOLISM, INDUCTION OF CELL DEATH, AND CHANGES IN MITOCHONDRIAL PERMEABILITY TRANSITION, THESE METABOLISM-RELATED CHANGES CAN LEAD TO MODULATION OF EPIGENETIC REGULATION OF GENE EXPRESSION. UNDERSTANDING THE NATURE OF THESE EPIGENETIC CHANGES WILL HELP RESEARCHERS DESIGN NOVEL MEDICATIONS TO TREAT OR AT LEAST AMELIORATE ALCOHOL-INDUCED ORGAN DAMAGE. 2013 8 128 35 A UNIFYING MECHANISM OF KETOGENIC DIET ACTION: THE MULTIPLE ROLES OF NICOTINAMIDE ADENINE DINUCLEOTIDE. THE ABILITY OF A KETOGENIC DIET TO TREAT SEIZURES AND RENDER A NEURONAL NETWORK MORE RESISTANT TO STRONG ELECTRICAL ACTIVITY HAS BEEN OBSERVED FOR A CENTURY IN CLINICS AND FOR DECADES IN RESEARCH LABORATORIES. ALONGSIDE ONGOING EFFORTS TO UNDERSTAND HOW THIS THERAPY WORKS TO STOP SEIZURES, METABOLIC HEALTH IS INCREASINGLY APPRECIATED AS CRITICAL BUFFER TO RESISTING AND RECOVERING FROM ACUTE AND CHRONIC DISEASE. ACCORDINGLY, LINKS BETWEEN METABOLISM AND HEALTH, AND THE BROADER EMERGING IMPACT OF THE KETOGENIC DIET IN IMPROVING DIVERSE METABOLIC, IMMUNOLOGICAL AND NEUROLOGICAL CONDITIONS, HAVE SERVED TO INTENSIFY THE SEARCH FOR ITS KEY AND/OR COMMON MECHANISMS. HERE WE REVIEW DIVERSE EVIDENCE FOR INCREASED LEVELS OF NAD(+), AND THUS AN ALTERED RATIO OF NAD(+)/NADH, DURING METABOLIC THERAPY WITH A KETOGENIC DIET. WE PROPOSE THIS AS A POTENTIAL UNIFYING MECHANISM, AND HIGHLIGHT SOME OF THE EVIDENCE LINKING ALTERED NAD(+)/NADH WITH REDUCED SEIZURES AND WITH A RANGE OF SHORT AND LONG-TERM CHANGES ASSOCIATED WITH THE BENEFICIAL EFFECTS OF A KETOGENIC DIET. AN INCREASE IN NAD(+)/NADH IS CONSISTENT WITH MULTIPLE LINES OF EVIDENCE AND HYPOTHESES, AND THEREFORE WE SUGGEST THAT INCREASED NAD(+) MAY BE A COMMON MECHANISM UNDERLYING BENEFICIAL EFFECTS OF KETOGENIC DIET THERAPY. 2020 9 5781 30 SPINAL SIRT1 ACTIVATION ATTENUATES NEUROPATHIC PAIN IN MICE. ABNORMAL HISTONE ACETYLATION OCCURS DURING NEUROPATHIC PAIN THROUGH AN EPIGENETIC MECHANISM. SILENT INFORMATION REGULATOR 1 (SIR2 OR SIRT1), A NAD-DEPENDENT DEACETYLASE, PLAYS COMPLEX SYSTEMIC ROLES IN A VARIETY OF PROCESSES THROUGH DEACETYLATING ACETYLATED HISTONE AND OTHER SPECIFIC SUBSTRATES. BUT THE ROLE OF SIRT1 IN NEUROPATHIC PAIN IS NOT WELL ESTABLISHED YET. THE PRESENT STUDY WAS INTENDED TO DETECT SIRT1 CONTENT AND ACTIVITY, NICOTINAMIDE (NAM) AND NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD) IN THE SPINAL CORD USING IMMUNOBLOTTING OR MASS SPECTROSCOPY OVER TIME IN MICE FOLLOWING CHRONIC CONSTRICTION INJURY (CCI) OR SHAM SURGERY. IN ADDITION, THE EFFECT OF INTRATHECAL INJECTION OF NAD OR RESVERATROL ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA WAS EVALUATED IN CCI MICE. FINALLY, WE INVESTIGATED WHETHER SIRT1 INHIBITOR EX-527 COULD REVERSE THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. IT WAS FOUND THAT SPINAL SIRT1 EXPRESSION, DEACETYLASE ACTIVITY AND NAD/NAM DECREASED SIGNIFICANTLY 1, 3, 7, 14 AND 21 DAYS AFTER CCI SURGERY AS COMPARED WITH SHAM GROUP. IN ADDITION, DAILY INTRATHECAL INJECTION OF 5 MICROL 800 MM NAD 1 H BEFORE AND 1 DAY AFTER CCI SURGERY OR SINGLE INTRATHECAL INJECTION OF 5 MICROL 90 MM RESVERATROL 1 H BEFORE CCI SURGERY PRODUCED A TRANSIENT INHIBITORY EFFECT ON THERMAL HYPERALGESIA AND MECHANICAL ALLODYNIA IN CCI MICE. FINALLY, AN INTRATHECAL INJECTION OF 5 MICROL 1.2 MM EX-527 1 H BEFORE NAD OR RESVERATROL ADMINISTRATION REVERSED THE ANTI-NOCICEPTIVE EFFECT OF NAD OR RESVERATROL. THESE DATA INDICATE THAT THE REDUCTION IN SIRT1 DEACETYLASE ACTIVITY MAY BE A FACTOR CONTRIBUTING TO THE DEVELOPMENT OF NEUROPATHIC PAIN IN CCI MICE. OUR FINDINGS SUGGEST THAT THE ENHANCEMENT OF SPINAL NAD/NAM AND/OR SIRT1 ACTIVITY MAY BE A POTENTIALLY PROMISING STRATEGY FOR THE PREVENTION OR TREATMENT OF NEUROPATHIC PAIN. 2014 10 4031 43 LYSINE DEACETYLASE (KDAC) REGULATORY PATHWAYS: AN ALTERNATIVE APPROACH TO SELECTIVE MODULATION. PROTEIN LYSINE DEACETYLASES (KDACS), INCLUDING THE CLASSIC ZN(2+) -DEPENDENT HISTONE DEACETYLASES (HDACS) AND THE NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+) )-REQUIRING SIRTUINS, ARE ENZYMES THAT PLAY CRITICAL ROLES IN NUMEROUS BIOLOGICAL PROCESSES, PARTICULARLY THE EPIGENETIC REGULATION OF GLOBAL GENE EXPRESSION PROGRAMS IN RESPONSE TO INTERNAL AND EXTERNAL CUES. DYSREGULATION OF KDACS IS CHARACTERISTIC OF SEVERAL HUMAN DISEASES, INCLUDING CHRONIC METABOLIC, NEURODEGENERATIVE, AND CARDIOVASCULAR DISEASES AND MANY CANCERS. THIS HAS LED TO THE DEVELOPMENT OF KDAC MODULATORS, TWO OF WHICH (HDAC INHIBITORS VORINOSTAT AND ROMIDEPSIN) HAVE BEEN APPROVED FOR THE TREATMENT OF CUTANEOUS T CELL LYMPHOMA. BY THEIR NATURE, EXISTING KDAC MODULATORS ARE RELATIVELY NONSPECIFIC, LEADING TO PAN-KDAC CHANGES AND UNDESIRED SIDE EFFECTS. GIVEN THAT KDACS ARE REGULATED AT MANY LEVELS, INCLUDING TRANSCRIPTIONAL, POST-TRANSLATIONAL, SUBCELLULAR LOCALIZATION, AND THROUGH THEIR COMPLEXATION WITH OTHER PROTEINS, IT SHOULD BE POSSIBLE TO AFFECT SPECIFIC KDAC ACTIVITY THROUGH MANIPULATION OF ENDOGENOUS SIGNALING PATHWAYS. IN THIS MINIREVIEW, WE DISCUSS OUR PRESENT KNOWLEDGE OF THE CELLULAR CONTROLS OF KDAC ACTIVITY AND EXAMPLES OF THEIR PHARMACOLOGIC REGULATION. 2014 11 5426 30 REGULATION OF SIRTUIN EXPRESSION IN AUTOIMMUNE NEUROINFLAMMATION: INDUCTION OF SIRT1 IN OLIGODENDROCYTE PROGENITOR CELLS. IN MULTIPLE SCLEROSIS (MS) REGENERATION OF OLIGODENDROCYTES FOLLOWING INFLAMMATORY DEMYELINATION IS LIMITED BY THE COMPROMISED ABILITY OF PROGENITORS TO REPOPULATE LESIONED AREAS AND TRANSITION TO FUNCTIONALLY COMPETENT OLIGODENDROCYTES. REGARDING UNDERLYING MECHANISMS, THE INVOLVEMENT OF EPIGENETIC PROCESSES HAS BEEN SUGGESTED, E.G. THE CONTRIBUTION OF HISTONE DEACETYLASES (HDAC) KNOWN TO REGULATE OLIGODENDROCYTE PROGENITOR CELL (OPC) DIFFERENTIATION. HOWEVER, THEIR PRECISE EXPRESSION PATTERNS, PARTICULAR OF REDOX-SENSITIVE NAD(+) HDACS, REMAINS LARGELY UNKNOWN. IN THIS STUDY, WE DETERMINED THE EXPRESSION AND ACTIVITY OF SIRTUINS, MEMBERS OF THE HDAC CLASS III FAMILY WITH A SPECIFIC FOCUS ON SIRT1, PREVIOUSLY ASSOCIATED WITH NEURODEGENERATIVE, INFLAMMATORY AND DEMYELINATING DISORDERS OF THE CENTRAL NERVOUS SYSTEM (CNS). BY INVESTIGATING MOUSE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE), A MODEL FOR MS, WE FOUND THAT TRANSCRIPTION OF SIRT1, SIRT2 AND SIRT6 WAS SIGNIFICANTLY INCREASED IN THE CNS DURING CHRONIC DISEASE STAGES. WE CONFIRMED THIS FINDING FOR SIRT1 PROTEIN EXPRESSION AND WERE ABLE TO LOCALIZE UPREGULATED SIRT1 IN NUCLEI OF NG2(+) OR PDGFRALPHA(+) OPCS IN DEMYELINATED BRAIN LESIONS. IN CULTURED MOUSE A2B5(+) OPCS BLOCKADE OF SIRT1 ACTIVITY BY THE SMALL MOLECULE COMPOUND EX527 ENHANCED MITOTIC ACTIVITY BUT DID NOT AFFECT THE CAPACITY TO DIFFERENTIATE. A SIMILAR PATTERN WAS DETECTABLE IN OPCS DERIVED FROM SIRT1-DEFICIENT ANIMALS. TAKEN TOGETHER, OUR DATA SUGGEST THAT SIRT1 INHIBITION MAY HELP TO EXPAND THE ENDOGENOUS POOL OF OPCS WITHOUT AFFECTING THEIR DIFFERENTIATION. 2019 12 5117 39 POSSIBLE ADVERSE EFFECTS OF HIGH-DOSE NICOTINAMIDE: MECHANISMS AND SAFETY ASSESSMENT. NICOTINAMIDE (NAM) AT DOSES FAR ABOVE THOSE RECOMMENDED FOR VITAMINS IS SUGGESTED TO BE EFFECTIVE AGAINST A WIDE SPECTRUM OF DISEASES AND CONDITIONS, INCLUDING NEUROLOGICAL DYSFUNCTIONS, DEPRESSION AND OTHER PSYCHOLOGICAL DISORDERS, AND INFLAMMATORY DISEASES. RECENT INCREASES IN PUBLIC AWARENESS ON POSSIBLE PRO-LONGEVITY EFFECTS OF NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) PRECURSORS HAVE CAUSED FURTHER GROWTH OF NAM CONSUMPTION NOT ONLY FOR CLINICAL TREATMENTS, BUT ALSO AS A DIETARY SUPPLEMENT, RAISING CONCERNS ON THE SAFETY OF ITS LONG-TERM USE. HOWEVER, POSSIBLE ADVERSE EFFECTS AND THEIR MECHANISMS ARE POORLY UNDERSTOOD. HIGH-LEVEL NAM ADMINISTRATION CAN EXERT NEGATIVE EFFECTS THROUGH MULTIPLE ROUTES. FOR EXAMPLE, NAM BY ITSELF INHIBITS POLY(ADP-RIBOSE) POLYMERASES (PARPS), WHICH PROTECT GENOME INTEGRITY. ELEVATION OF THE NAD(+) POOL ALTERS CELLULAR ENERGY METABOLISM. MEANWHILE, HIGH-LEVEL NAM ALTERS CELLULAR METHYL METABOLISM AND AFFECTS METHYLATION OF DNA AND PROTEINS, LEADING TO CHANGES IN CELLULAR TRANSCRIPTOME AND PROTEOME. ALSO, METHYL METABOLITES OF NAM, NAMELY METHYLNICOTINAMIDE, ARE PREDICTED TO PLAY ROLES IN CERTAIN DISEASES AND CONDITIONS. IN THIS REVIEW, A COLLECTIVE LITERATURE SEARCH WAS PERFORMED TO PROVIDE A COMPREHENSIVE LIST OF POSSIBLE ADVERSE EFFECTS OF NAM AND TO PROVIDE UNDERSTANDING OF THEIR UNDERLYING MECHANISMS AND ASSESSMENT OF THE RAISED SAFETY CONCERNS. OUR REVIEW ASSURES SAFETY IN CURRENT USAGE LEVEL OF NAM, BUT ALSO FINDS POTENTIAL RISKS FOR EPIGENETIC ALTERATIONS ASSOCIATED WITH CHRONIC USE OF NAM AT HIGH DOSES. IT ALSO SUGGESTS DIRECTIONS OF THE FUTURE STUDIES TO ENSURE SAFER APPLICATION OF NAM. 2020 13 4037 26 MACROPHAGE IMMUNOMETABOLISM AND INFLAMMAGING: ROLES OF MITOCHONDRIAL DYSFUNCTION, CELLULAR SENESCENCE, CD38, AND NAD. AGING IS A COMPLEX PROCESS THAT INVOLVES DYSFUNCTION ON MULTIPLE LEVELS, ALL OF WHICH SEEM TO CONVERGE ON INFLAMMATION. MACROPHAGES ARE INTIMATELY INVOLVED IN INITIATING AND RESOLVING INFLAMMATION, AND THEIR DYSREGULATION WITH AGE IS A PRIMARY CONTRIBUTOR TO INFLAMMAGING-A STATE OF CHRONIC, LOW-GRADE INFLAMMATION THAT DEVELOPS DURING AGING. AMONG THE AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES ARE A HEIGHTENED STATE OF BASAL INFLAMMATION AND DIMINISHED OR HYPERACTIVE INFLAMMATORY RESPONSES, WHICH SEEM TO BE DRIVEN BY METABOLIC-DEPENDENT EPIGENETIC CHANGES. IN THIS REVIEW ARTICLE WE PROVIDE A BRIEF OVERVIEW OF MITOCHONDRIAL FUNCTIONS AND AGE-RELATED CHANGES THAT OCCUR TO MACROPHAGES, WITH AN EMPHASIS ON HOW THE INFLAMMAGING ENVIRONMENT, SENESCENCE, AND NAD DECLINE CAN AFFECT THEIR METABOLISM, PROMOTE DYSREGULATION, AND CONTRIBUTE TO INFLAMMAGING AND AGE-RELATED PATHOLOGIES. 2020 14 6103 43 THE EMERGING ROLE OF HDACS: PATHOLOGY AND THERAPEUTIC TARGETS IN DIABETES MELLITUS. DIABETES MELLITUS (DM) IS ONE OF THE PRINCIPAL MANIFESTATIONS OF METABOLIC SYNDROME AND ITS PREVALENCE WITH MODERN LIFESTYLE IS INCREASING INCESSANTLY. CHRONIC HYPERGLYCEMIA CAN INDUCE SEVERAL VASCULAR COMPLICATIONS THAT WERE REFERRED TO BE THE MAJOR CAUSE OF MORBIDITY AND MORTALITY IN DM. ALTHOUGH SEVERAL THERAPEUTIC TARGETS HAVE BEEN IDENTIFIED AND ACCESSED CLINICALLY, THE IMMINENT RISK OF DM AND ITS PREVALENCE ARE STILL ASCENDING. SUBSTANTIAL PIECES OF EVIDENCE REVEALED THAT HISTONE DEACETYLASE (HDAC) ISOFORMS CAN REGULATE VARIOUS MOLECULAR ACTIVITIES IN DM VIA EPIGENETIC AND POST-TRANSLATIONAL REGULATION OF SEVERAL TRANSCRIPTION FACTORS. TO DATE, 18 HDAC ISOFORMS HAVE BEEN IDENTIFIED IN MAMMALS THAT WERE CATEGORIZED INTO FOUR DIFFERENT CLASSES. CLASSES I, II, AND IV ARE REGARDED AS CLASSICAL HDACS, WHICH OPERATE THROUGH A ZN-BASED MECHANISM. IN CONTRAST, CLASS III HDACS OR SIRTUINS DEPEND ON NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD(+)) FOR THEIR MOLECULAR ACTIVITY. FUNCTIONALLY, MOST OF THE HDAC ISOFORMS CAN REGULATE BETA CELL FATE, INSULIN RELEASE, INSULIN EXPRESSION AND SIGNALING, AND GLUCOSE METABOLISM. MOREOVER, THE ROLES OF HDAC MEMBERS HAVE BEEN IMPLICATED IN THE REGULATION OF OXIDATIVE STRESS, INFLAMMATION, APOPTOSIS, FIBROSIS, AND OTHER PATHOLOGICAL EVENTS, WHICH SUBSTANTIALLY CONTRIBUTE TO DIABETES-RELATED VASCULAR DYSFUNCTIONS. THEREFORE, HDACS COULD SERVE AS THE POTENTIAL THERAPEUTIC TARGET IN DM TOWARDS DEVELOPING NOVEL INTERVENTION STRATEGIES. THIS REVIEW SHEDS LIGHT ON THE EMERGING ROLE OF HDACS/ISOFORMS IN DIABETIC PATHOPHYSIOLOGY AND EMPHASIZED THE SCOPE OF THEIR TARGETING IN DM FOR CONSTITUTING NOVEL INTERVENTIONAL STRATEGIES FOR METABOLIC DISORDERS/COMPLICATIONS. 2021 15 5711 35 SIRT1 IS A HIGHLY NETWORKED PROTEIN THAT MEDIATES THE ADAPTATION TO CHRONIC PHYSIOLOGICAL STRESS. SIRT1 IS A NAD(+)-DEPENDENT PROTEIN DEACETYLASE THAT HAS A VERY LARGE NUMBER OF ESTABLISHED PROTEIN SUBSTRATES AND AN EQUALLY IMPRESSIVE LIST OF BIOLOGICAL FUNCTIONS THOUGHT TO BE REGULATED BY ITS ACTIVITY. PERHAPS AS NOTABLE IS THE REMARKABLE NUMBER OF POINTS OF CONFLICT CONCERNING THE ROLE OF SIRT1 IN BIOLOGICAL PROCESSES. FOR EXAMPLE, EVIDENCE EXISTS SUGGESTING THAT SIRT1 IS A TUMOR SUPPRESSOR, IS AN ONCOGENE, OR HAS NO EFFECT ON ONCOGENESIS. SIMILARLY, SIRT1 IS VARIABLY REPORTED TO INDUCE, INHIBIT, OR HAVE NO EFFECT ON AUTOPHAGY. WE BELIEVE THAT THE RESOLUTION OF MANY CONFLICTING RESULTS IS POSSIBLE BY CONSIDERING RECENT REPORTS INDICATING THAT SIRT1 IS AN IMPORTANT HUB INTERACTING WITH A COMPLEX NETWORK OF PROTEINS THAT COLLECTIVELY REGULATE A WIDE VARIETY OF BIOLOGICAL PROCESSES INCLUDING CANCER AND AUTOPHAGY. A NUMBER OF THE INTERACTING PROTEINS ARE THEMSELVES HUBS THAT, LIKE SIRT1, UTILIZE INTRINSICALLY DISORDERED REGIONS FOR THEIR PROMISCUOUS INTERACTIONS. MANY STUDIES INVESTIGATING SIRT1 FUNCTION HAVE BEEN CARRIED OUT ON CELL LINES CARRYING UNDETERMINED NUMBERS OF ALTERATIONS TO THE PROTEINS COMPRISING THE SIRT1 NETWORK OR ON INBRED MOUSE STRAINS CARRYING FIXED MUTATIONS AFFECTING SOME OF THESE PROTEINS. THUS, THE EFFECTS OF MODULATING SIRT1 AMOUNT AND/OR ACTIVITY ARE IMPORTANTLY DETERMINED BY THE GENETIC BACKGROUND OF THE CELL (OR THE INBRED STRAIN OF MICE), AND THE EFFECTS ATTRIBUTED TO SIRT1 ARE SYNTHETIC WITH THE BACKGROUND OF MUTATIONS AND EPIGENETIC DIFFERENCES BETWEEN CELLS AND ORGANISMS. WORK ON MICE CARRYING ALTERATIONS TO THE SIRT1 GENE SUGGESTS THAT THE NETWORK IN WHICH SIRT1 FUNCTIONS PLAYS AN IMPORTANT ROLE IN MEDIATING PHYSIOLOGICAL ADAPTATION TO VARIOUS SOURCES OF CHRONIC STRESS SUCH AS CALORIE RESTRICTION AND CALORIE OVERLOAD. WHETHER THE CATALYTIC ACTIVITY OF SIRT1 AND THE NUCLEAR CONCENTRATION OF THE CO-FACTOR, NAD(+), ARE RESPONSIBLE FOR MODULATING THIS ACTIVITY REMAINS TO BE DETERMINED. HOWEVER, THE EFFECT OF MODULATING SIRT1 ACTIVITY MUST BE INTERPRETED IN THE CONTEXT OF THE CELL OR TISSUE UNDER INVESTIGATION. INDEED, FOR SIRT1, WE ARGUE THAT CONTEXT IS EVERYTHING. 2013 16 5986 38 TFEB IS A CENTRAL REGULATOR OF THE AGING PROCESS AND AGE-RELATED DISEASES. OLD AGE IS ASSOCIATED WITH A GREATER BURDEN OF DISEASE, INCLUDING NEURODEGENERATIVE DISORDERS SUCH AS ALZHEIMER'S DISEASE AND PARKINSON'S DISEASE, AS WELL AS OTHER CHRONIC DISEASES. COINCIDENTALLY, POPULAR LIFESTYLE INTERVENTIONS, SUCH AS CALORIC RESTRICTION, INTERMITTENT FASTING, AND REGULAR EXERCISE, IN ADDITION TO PHARMACOLOGICAL INTERVENTIONS INTENDED TO PROTECT AGAINST AGE-RELATED DISEASES, INDUCE TRANSCRIPTION FACTOR EB (TFEB) AND AUTOPHAGY. IN THIS REVIEW, WE SUMMARIZE EMERGING DISCOVERIES THAT POINT TO TFEB ACTIVITY AFFECTING THE HALLMARKS OF AGING, INCLUDING INHIBITING DNA DAMAGE AND EPIGENETIC MODIFICATIONS, INDUCING AUTOPHAGY AND CELL CLEARANCE TO PROMOTE PROTEOSTASIS, REGULATING MITOCHONDRIAL QUALITY CONTROL, LINKING NUTRIENT-SENSING TO ENERGY METABOLISM, REGULATING PRO- AND ANTI-INFLAMMATORY PATHWAYS, INHIBITING SENESCENCE AND PROMOTING CELL REGENERATIVE CAPACITY. FURTHERMORE, THE THERAPEUTIC IMPACT OF TFEB ACTIVATION ON NORMAL AGING AND TISSUE-SPECIFIC DISEASE DEVELOPMENT IS ASSESSED IN THE CONTEXTS OF NEURODEGENERATION AND NEUROPLASTICITY, STEM CELL DIFFERENTIATION, IMMUNE RESPONSES, MUSCLE ENERGY ADAPTATION, ADIPOSE TISSUE BROWNING, HEPATIC FUNCTIONS, BONE REMODELING, AND CANCER. SAFE AND EFFECTIVE STRATEGIES OF ACTIVATING TFEB HOLD PROMISE AS A THERAPEUTIC STRATEGY FOR MULTIPLE AGE-ASSOCIATED DISEASES AND FOR EXTENDING LIFESPAN. 2023 17 5591 28 ROLE OF THE EPIGENETIC FACTOR SIRT7 IN NEUROINFLAMMATION AND NEUROGENESIS. EPIGENETIC REGULATORS ARE INCREASINGLY RECOGNIZED AS RELEVANT MODULATORS IN THE IMMUNE AND NERVOUS SYSTEM. THE CLASS OF SIRTUINS CONSISTS OF NAD(+)-DEPENDENT HISTONE DEACETYLASES THAT REGULATE TRANSCRIPTION. SIRTUIN FAMILY MEMBER SIRT1 HAS ALREADY BEEN SHOWN TO INFLUENCE THE DISEASE COURSE IN AN ANIMAL MODEL OF AUTOIMMUNE NEUROINFLAMMATION (EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS (EAE). A ROLE OF SIRT7, A RELATED EPIGENETIC REGULATOR, ON IMMUNE SYSTEM REGULATION HAS BEEN PROPOSED BEFORE, AS THESE MICE ARE MORE SUSCEPTIBLE TO DEVELOP INFLAMMATORY CARDIOMYOPATHY. SIRT7(-/-) ANIMALS SHOWED NO DIFFERENCES IN CLINICAL SCORE COMPARED TO WILD-TYPE LITTERMATES AFTER EAE INDUCTION WITH MYELIN OLIGODENDROCYTE GLYCOPROTEIN (MOG) PEPTIDE (35-55), ALTHOUGH WE FOUND SUBTLE IMMUNE ALTERATIONS AT DIFFERENT PHASES OF EAE AND DECREASED SURVIVAL OF NEWLY GENERATED NEURONS IN THE HIPPOCAMPUS. OUR DATA INDICATE THAT SIRT7 HAS A SLIGHT PROTECTIVE IMPACT ON BOTH THE ADAPTIVE IMMUNE SYSTEM AND NEUROGENESIS. HOWEVER, OVERALL THIS EPIGENETIC FACTOR IS NOT CAPABLE OF IMPACTING THE ACUTE OR CHRONIC PHASE OF NEUROINFLAMMATION. 2018 18 4772 29 NUCLEAR SIRTUINS AND INFLAMMATORY SIGNALING PATHWAYS. THE REGULATION OF CHRONIC INFLAMMATION HAS RECEIVED CONSIDERABLE RESEARCH ATTENTION IN RECENT YEARS BECAUSE OF ITS CONTRIBUTION TO THE PATHOGENESIS OF CHRONIC DISEASES SUCH AS ARTHRITIS, DIABETES, METABOLIC SYNDROME AND OBESITY. THUS, STRATEGIES THAT INHIBIT THE INFLAMMATORY STATE MAY BE BENEFICIAL IN IMPROVING THE PATHOPHYSIOLOGY OF SEVERAL INFLAMMATION-RELATED DISORDERS. SIRTUINS ARE A FAMILY OF HISTONE DEACETYLASES THAT CONTAIN SEVEN ENZYMATIC ACTIVITIES IN MAMMALS (SIRT1-SIRT7) AND FUNCTION TO SUPPRESS GENE TRANSCRIPTION BY EPIGENETIC MECHANISMS. NUCLEAR SIRTUINS (SIRT 1, 2, 6 AND 7) IN PARTICULAR MAY PLAY AN IMPORTANT ROLE IN THE REGULATION OF INFLAMMATORY RESPONSES. IN THE PRESENT REVIEW, WE ASSESSED THE ROLES OF NUCLEAR SIRTUINS IN INFLAMMATORY REACTIONS: SIRT1 HAS BEEN SHOWN TO SUPPRESS NF-KAPPAB ACTIVITY, THE MASTER REGULATOR OF CELLULAR INFLAMMATORY RESPONSE, DECREASE COX-2 AND INOS PRODUCTION, AND INCREASE ANTIOXIDANT GENE EXPRESSION THAT SUPPRESSED INFLAMMATION. SIRT2 ACTIVITY INCLUDED THE DEACETYLATION OF P65 SUBUNIT OF NF-KAPPABETA AND RIP-1, WHILE SIRT6 HAS BEEN SHOWN TO INTERACT WITH P65/RELA BOUND TO THE NF-KAPPABETA PROMOTER REGION AND REPRESS TRANSCRIPTIONAL ACTIVITY. FURTHERMORE, RECENT STUDIES HAVE SHOWN THAT THE ABSENCE OF SIRT7 PRODUCED AN INCREASE IN INFLAMMATION, ILLUSTRATING THAT SIRT7 ALSO FUNCTIONED TO DECREASE INFLAMMATION. GIVEN THEIR SIGNIFICANT ROLES IN THE REGULATION OF CHRONIC INFLAMMATION, NUCLEAR SIRTUINS REPRESENT POTENTIAL THERAPEUTIC TARGETS IN THE CONTROL OF CHRONIC INFLAMMATORY DISEASES. 2017 19 6041 27 THE CLASS III HISTONE DEACETYLASE SIRTUIN 1 IN IMMUNE SUPPRESSION AND ITS THERAPEUTIC POTENTIAL IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC DEBILITATING DISEASE OF THE JOINTS. BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSES PARTICIPATE IN THE DEVELOPMENT AND PROGRESSION OF RA. WHILE SEVERAL THERAPEUTIC REAGENTS, SUCH AS TNF-ALPHA AGONISTS, HAVE BEEN SUCCESSFULLY DEVELOPED FOR THE CLINICAL USE IN THE TREATMENT OF RA, MORE THAN HALF OF THE PATIENTS DO NOT RESPOND TO ANTI-TNF THERAPY. THEREFORE, NEW THERAPEUTIC REAGENTS ARE NEEDED. RECENT STUDIES HAVE SHOWN THAT SIRTUIN 1 (SIRT1), A NICOTINAMIDE ADENINE DINUCLEOTIDE (NAD)-DEPENDENT HISTONE DEACETYLASE, IS A CRITICAL NEGATIVE REGULATOR OF BOTH THE INNATE AND ADAPTIVE IMMUNE RESPONSE IN MICE, AND ITS ALTERED FUNCTIONS ARE LIKELY TO BE INVOLVED IN AUTOIMMUNE DISEASES. SMALL MOLECULES THAT MODULATE SIRT1 FUNCTIONS ARE POTENTIAL THERAPEUTIC REAGENTS FOR AUTOIMMUNE INFLAMMATORY DISEASES. THIS REVIEW HIGHLIGHTS THE ROLE OF SIRT1 IN IMMUNE REGULATION AND RA. 2013 20 375 23 AN ENERGETIC VIEW OF STRESS: FOCUS ON MITOCHONDRIA. ENERGY IS REQUIRED TO SUSTAIN LIFE AND ENABLE STRESS ADAPTATION. AT THE CELLULAR LEVEL, ENERGY IS LARGELY DERIVED FROM MITOCHONDRIA - UNIQUE MULTIFUNCTIONAL ORGANELLES WITH THEIR OWN GENOME. FOUR MAIN ELEMENTS CONNECT MITOCHONDRIA TO STRESS: (1) ENERGY IS REQUIRED AT THE MOLECULAR, (EPI)GENETIC, CELLULAR, ORGANELLAR, AND SYSTEMIC LEVELS TO SUSTAIN COMPONENTS OF STRESS RESPONSES; (2) GLUCOCORTICOIDS AND OTHER STEROID HORMONES ARE PRODUCED AND METABOLIZED BY MITOCHONDRIA; (3) RECIPROCALLY, MITOCHONDRIA RESPOND TO NEUROENDOCRINE AND METABOLIC STRESS MEDIATORS; AND (4) EXPERIMENTALLY MANIPULATING MITOCHONDRIAL FUNCTIONS ALTERS PHYSIOLOGICAL AND BEHAVIORAL RESPONSES TO PSYCHOLOGICAL STRESS. THUS, MITOCHONDRIA ARE ENDOCRINE ORGANELLES THAT PROVIDE BOTH THE ENERGY AND SIGNALS THAT ENABLE AND DIRECT STRESS ADAPTATION. NEURAL CIRCUITS REGULATING SOCIAL BEHAVIOR - AS WELL AS PSYCHOPATHOLOGICAL PROCESSES - ARE ALSO INFLUENCED BY MITOCHONDRIAL ENERGETICS. AN INTEGRATIVE VIEW OF STRESS AS AN ENERGY-DRIVEN PROCESS OPENS NEW OPPORTUNITIES TO STUDY MECHANISMS OF ADAPTATION AND REGULATION ACROSS THE LIFESPAN. 2018