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The Biology of Aging and Frailty

      Keywords

      In developing and validating the concept of frailty as a geriatric syndrome, it has been necessary to distinguish the clinical expression of frailty from normal age-related changes and other age-related disease pathologies. Fried and colleagues
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      • Walston J.
      • McBurnie M.A.
      • Newman A.
      • et al.
      Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
      • Fried L.P.
      • Ferrucci L.
      • Darer J.
      • et al.
      Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care.
      • Bandeen-Roche K.
      • Xue Q.L.
      • Ferrucci L.
      • et al.
      Phenotype of frailty: characterization in the women’s health and aging studies.
      • Chang S.S.
      • Weiss C.O.
      • Xue Q.L.
      • et al.
      Patterns of comorbid inflammatory diseases in frail older women: the Women’s Health and Aging Studies I and II.
      have provided a framework for excluding potentially confounding disease and a working clinical tool to diagnose frailty, and they have shown associations between frailty and other pathophysiologies. However, investigating the underlying biologic basis for the geriatric syndrome of frailty by studying basic homeostatic pathways and mechanisms has not proceeded at the same rate. The following article provides an overview of the homeostatic pathways emphasized in research on aging and explains how this science may help to stimulate frailty research.

      Normal aging

      Aging can be defined as the decline and deterioration of functional properties at the cellular, tissue, and organ level. This loss of functional properties yields a loss of homeostasis and a decreased adaptability to internal and external stress, increasing vulnerability to disease and mortality.

      Holliday R, Understanding ageing. Developmental and cell biology series; 30. Cambridge (UK); New York: Cambridge University Press; 1995. p. xiv, 207.

      Aging is a breakdown in maintenance of specific molecular structures and pathways, a loss of homeostasis, and a failure in homeodynamics.
      • Lloyd D.
      • Aon M.A.
      • Cortassa S.
      Why homeodynamics, not homeostasis?.
      Homeodynamics refers to biologic systems that do not actively mandate stasis; instead, they dynamically reorganize and reset points of balance in response to internal and external change to maintain their functional capacity over time.
      Individuals vary a great deal in the onset of the aging process and the rate and extent of its progression. Differences in the manifestations of aging reflect differences in functional capacity. Functional capacity is a direct measure of the ability of cells, tissues, and organ systems to operate properly/optimally and is influenced by genes and environment. Optimal cellular, organ, and organism operation reflects homeodynamic mechanisms and maintenance pathways. Mechanisms of maintenance include DNA repair, synthesis, and fidelity surveillance; detection and clearance of defective proteins and lipids; clearance of defective organelles and cells; and defense against pathogens and injury. Many of the physiologic theories of aging are direct counterparts of these maintenance mechanisms (eg, DNA damage, error catastrophe, free-radical, mitochondrial damage, and immunosenescence theories). These maintenance mechanisms, in turn, affect homeodynamics through the cellular responses of apoptosis, senescence, and repair and the systemic response of immune activation/inflammation. For example, when DNA damage is too great to be repaired, cells undergo apoptosis.
      • Roos W.P.
      • Kaina B.
      DNA damage-induced cell death by apoptosis.
      Cells can respond to free-radical damage to DNA by inducing senescence
      • Chen Q.
      • Fischer A.
      • Reagan J.D.
      • et al.
      Oxidative DNA damage and senescence of human diploid fibroblast cells.
      or initiating apoptosis.
      • Ozawa T.
      Oxidative damage and fragmentation of mitochondrial DNA in cellular apoptosis.
      Oxidative damage and apoptosis are correlated negatively with the repair mechanism autophagy.
      • Wohlgemuth S.E.
      • Seo A.Y.
      • Marzetti E.
      • et al.
      Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise.
      Proteins aberrantly modified with nonenzymatic glycation
      • Ramasamy R.
      • Vannucci S.J.
      • Yan S.S.
      • et al.
      Advanced glycation end products and RAGE: a common thread in aging, diabetes, neurodegeneration, and inflammation.
      or free radicals
      • Nabeshi H.
      • Oikawa S.
      • Inoue S.
      • et al.
      Proteomic analysis for protein carbonyl as an indicator of oxidative damage in senescence-accelerated mice.
      can induce inflammation. Inflammation and immune responses resolve, in part, through targeted immune cell apoptosis.
      • Marshall J.C.
      • Watson R.W.
      Programmed cell death (apoptosis) and the resolution of systemic inflammation.
      In addition to critical telomere length, senescence can be triggered by oxidative stress
      • Chen Q.
      • Fischer A.
      • Reagan J.D.
      • et al.
      Oxidative DNA damage and senescence of human diploid fibroblast cells.
      • von Zglinicki T.
      Role of oxidative stress in telomere length regulation and replicative senescence.
      and protein glycation/cross-links.
      • Nagaraj R.H.
      • Sell D.R.
      • Prabhakaram M.
      • et al.
      High correlation between pentosidine protein crosslinks and pigmentation implicates ascorbate oxidation in human lens senescence and cataractogenesis.
      • Ravelojaona V.
      • Robert A.M.
      • Robert L.
      Expression of senescence-associated beta-galactosidase (SA-beta-Gal) by human skin fibroblasts, effect of advanced glycation end-products and fucose or rhamnose-rich polysaccharides.
      Hormones contribute to homeodynamics, in part, through modulation of apoptosis, senescence, and inflammation.
      • Evans-Storms R.B.
      • Cidlowski J.A.
      Regulation of apoptosis by steroid hormones.
      • Hertoghe T.
      The “multiple hormone deficiency” theory of aging: is human senescence caused mainly by multiple hormone deficiencies?.
      • Roubenoff R.
      Molecular basis of inflammation: relationships between catabolic cytokines, hormones, energy balance, and muscle.

      Frailty

      Frailty is a geriatric syndrome characterized by weakness, weight loss, and low activity and is associated with adverse health outcomes. Frailty manifests as age-related, biologic vulnerability to stressors and decreased physiologic reserves yielding a limited capacity to maintain homeostasis.
      • Fried L.P.
      • Ferrucci L.
      • Darer J.
      • et al.
      Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care.
      The validated and widely used 5-item frailty criteria for screening—self-reported exhaustion, slowed performance (by walking speed), weakness (by grip strength), unintentional weight loss (4.5 kg in the past year), and low physical activity
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      —are composite outcomes of multiple organ systems. The surrogate endpoint markers—elevated cytokines and chemokines
      • Leng S.
      • Chaves P.
      • Koenig K.
      • et al.
      Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study.
      • De Martinis M.
      • Franceschi C.
      • Monti D.
      • et al.
      Inflammation markers predicting frailty and mortality in the elderly.
      • Qu T.
      • Yang H.
      • Walston J.D.
      • et al.
      Upregulated monocytic expression of CXC chemokine ligand 10 (CXCL-10) and its relationship with serum interleukin-6 levels in the syndrome of frailty.
      ; reduced insulinlike growth factor 1(IGF-I), dehydroepiandrosterone sulfate, and leptin
      • Hubbard R.E.
      • O’Mahony M.S.
      • Calver B.L.
      • et al.
      Plasma esterases and inflammation in ageing and frailty.
      ; perturbed neutrophil, monocyte, and white blood cell distribution
      • Leng S.X.
      • Xue Q.L.
      • Tian J.
      • et al.
      Inflammation and frailty in older women.
      • Leng S.X.
      • Xue Q.L.
      • Tian J.
      • et al.
      Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I.
      —indicate multiple systems are dysregulated in frailty.
      This definition of frailty (multisystem dysregulation yielding decreased physiologic reserves and increased vulnerability to stressors) has commonality to that of aging (loss of molecular/cellular functional properties yielding decreased adaptability to internal/external stress and increased vulnerability to disease and mortality). Both have a basis in loss of homeostasis, although with aging, the failure in homeodynamics is global, whereas with frailty, the failure in homeodynamics cycle around energy metabolism and neuromuscular changes. Because researchers have characterized frail elderly populations, the observed changes in functional performance and biomarker distribution are distinct from the corresponding age-related changes observed in nonfrail (normal) individuals.
      • Fried L.P.
      • Tangen C.M.
      • Walston J.
      • et al.
      Frailty in older adults: evidence for a phenotype.
      • Walston J.
      • McBurnie M.A.
      • Newman A.
      • et al.
      Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
      • Fried L.P.
      • Ferrucci L.
      • Darer J.
      • et al.
      Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care.
      • Bandeen-Roche K.
      • Xue Q.L.
      • Ferrucci L.
      • et al.
      Phenotype of frailty: characterization in the women’s health and aging studies.

      Cellular responses to stressors

      For aging and frailty, loss of homeostasis results in an increased vulnerability to stressors. An organism’s reaction to stressors involves the cellular responses of apoptosis, senescence, and repair. At the cellular level, stressors (eg, free radicals, DNA damage, cell injury/insult) challenge maintenance mechanisms (Fig. 1). The evolved cellular response, apoptosis, removes damaged/aberrant cells through controlled cell death; senescence alters their phenotype and blocks further proliferation; and repair removes damaged proteins, lipids, and organelles and recycles constituent parts. Failure in these responses leads to transformed cells/neoplasms that can radically compromise organ function and survival. Dysregulation of these cellular responses can contribute to tissue pathology when, for example, increased apoptosis leads to tissue/organ atrophy or when expression of the senescent cell phenotype increases proinflammatory cytokine release. All these cellular responses have been implicated in normal aging and are discussed in greater detail in the following sections. The balance between apoptosis and senescence or the acceleration of either may well precipitate changes in multiple systems and, ultimately, in frailty and related late-life vulnerability.
      Figure thumbnail gr1
      Fig. 1Cellular responses to stressors. Stressors (free radicals, DNA damage, nutrient or oxygen constriction, cell injury [represented by the lightening bolt]) challenge cellular homeostasis. The cellular response can be senescence, apoptosis, repair, or neoplastic transformation of the cell. Senescence, a tumor-suppressive response is associated with an altered secretory phenotype. The controlled cell death of apoptosis can also be tumor-suppressive, although many cells, especially immune cells, normally exit through apoptosis. Apoptosis can, however, yield tissue/organ atrophy. Repair enables recovery of homeostasis. In some cases, apoptosis is a precursor of repair and recovery (dotted line with arrow). Also, the senescent cell phenotype is sometimes a precursor/contributor to neoplasm formation and cancer progression.

      Apoptosis

      Apoptosis is an orderly process of cellular self-destruction, a process as crucial for survival of multicellular organisms as cell division. Apoptosis is important in embryogenesis: morphogenesis (eliminating excess cells, such as webbing between digits in embryos), selection (eliminating nonfunctional cells, as in neuronal pruning), immunity (eliminating dangerous cells, such as self-antigen recognizing cells), and organ size (eliminating excess cells).
      • Haanen C.
      • Vermes I.
      Apoptosis: programmed cell death in fetal development.
      Apoptosis is also important in adults in tissue remodeling (eliminating cells no longer needed, as in mammary gland involution after lactation), maintains organ size and function,
      • Mondello C.
      • Scovassi A.I.
      Apoptosis: a way to maintain healthy individuals.
      and eliminates damaged/dysfunctional cells.
      • Muradian K.
      • Schachtschabel D.O.
      The role of apoptosis in aging and age-related disease: update.
      • Pollack M.
      • Phaneuf S.
      • Dirks A.
      • et al.
      The role of apoptosis in the normal aging brain, skeletal muscle, and heart.
      Apoptosis can be initiated by external signals that bind to physiologic receptors on cell surfaces or by intrinsic damage that propagates cytosolic signals. Both pathways converge with mitochondrial signals, which lead to a caspase cleavage cascade, which, in turn, results in the orderly proteolysis of proteins and DNA, the cross-linking of cell corpses, and their subsequent engulfment. Although death by necrosis and oncosis (ischemic cell death) invokes major inflammatory responses and collateral damage, apoptosis is a controlled cellular demolition with no inflammatory response. Key apoptosis steps (chromatin condensation, vesicle formation, and activity of hydrolytic enzymes) have a high energy demand and thus, apoptosis is an adenosine triphosphate (ATP)-dependent process.
      • Kass G.E.
      • Eriksson J.E.
      • Weis M.
      • et al.
      Chromatin condensation during apoptosis requires ATP.
      Thus, at insufficient ATP levels, cells shift from apoptotic to necrotic cell death.
      • Richter C.
      • Schweizer M.
      • Cossarizza A.
      • et al.
      Control of apoptosis by the cellular ATP level.
      Consistent with this, an age-related decline in cellular ATP levels was found to promote necrotic fibroblast cell death over apoptosis in response to oxidative stress.
      • Miyoshi N.
      • Oubrahim H.
      • Chock P.B.
      • et al.
      Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis.
      These molecular processes may stimulate chronic inflammation in older adults, which probably facilitates frailty and late-life decline through mechanisms discussed below.
      As a sentinel homeodynamic cellular response, apoptosis can have pathophysiologic consequences for aging. For example, too much apoptosis can yield tissue degeneration,
      • Adams J.D.
      • Mukherjee S.K.
      • Klaidman L.K.
      • et al.
      Apoptosis and oxidative stress in the aging brain.
      whereas too little apoptosis allows dysfunctional cells to accumulate or differentiated immune cells to persist.
      • Gupta S.
      Molecular mechanisms of apoptosis in the cells of the immune system in human aging.
      Evidence suggests that sarcopenia is apoptosis-driven.
      • Marzetti E.
      • Leeuwenburgh C.
      Skeletal muscle apoptosis, sarcopenia and frailty at old age.
      Conversely, failures in apoptosis can contribute to the senescent cell phenotype as well as rogue cell proliferation.
      • Hsu H.C.
      • Scott D.K.
      • Mountz J.D.
      Impaired apoptosis and immune senescence - cause or effect?.
      It has been shown that apoptosis is an important cellular defense mechanism in maintaining genetic stability, and centenarians who have aged successfully possess cells that are more prone to apoptosis.
      • Franceschi C.
      • Monti D.
      • Scarfi M.R.
      • et al.
      Genomic instability and aging. Studies in centenarians (successful aging) and in patients with Down’s syndrome (accelerated aging).
      The proinflammatory marker interleukin 6 (IL-6) seems to be protective against apoptosis
      • Biffl W.L.
      • Moore E.E.
      • Moore F.A.
      • et al.
      Interleukin-6 delays neutrophil apoptosis.
      and its serum levels are known to increase with increasing age
      • Giuliani N.
      • Sansoni P.
      • Girasole G.
      • et al.
      Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes.
      and have an inverse correlation with apoptosis.
      • Kovalovich K.
      • Li W.
      • DeAngelis R.
      • et al.
      Interleukin-6 protects against Fas-mediated death by establishing a critical level of anti-apoptotic hepatic proteins FLIP, Bcl-2, and Bcl-xL.

      Senescence

      Cellular senescence is a response of normal cells to potentially cancer-causing events. The term replicative senescence identifies the subset of senescent cells in which the arrest in proliferation is associated with the high number of cell divisions (the Hayflick and Moorhead
      • Hayflick L.
      • Moorhead P.S.
      The serial cultivation of human diploid cell strains.
      limit—typically between 40 and 60 cell divisions). The mechanism for replicative senescence involves each division resulting in a shortening of the telomere region of chromosomes, such that a cumulative critical length is reached that does not support the DNA replication machinery. Senescent cells exhibit an irreversible arrest of cell proliferation, an altered function, and in some cases, a resistance to apoptosis. Besides telomere shortening, inducers of senescence include DNA damage, oncogene expression, supermitogenic signals,
      • Muller M.
      Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations.
      and telomere-independent pathways, which include cytoskeletal, interferon-related, IGF-related, mitogen-activated protein kinase, and oxidative stress pathways.
      • Fridman A.L.
      • Tainsky M.A.
      Critical pathways in cellular senescence and immortalization revealed by gene expression profiling.
      The arrest in proliferation is imposed and maintained on cells by the induction of cyclin-dependent kinase inhibitors p16 and p21 that implement cell-cycle arrest.
      • Ohtani N.
      • Yamakoshi K.
      • Takahashi A.
      • et al.
      The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression.
      Cellular senescence is associated with typical phenotypic changes, such as enlarged morphology, activation of senescence-associated β-galactosidase, elevated expression of proteases, cell-cycle inhibitors, and proinflammatory cytokines.
      • Muller M.
      Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations.
      The contribution of cellular (replicative) senescence to organismal aging has been controversial, although increasingly; evidence seems to link cellular senescence to aging.
      • Campisi J.
      Cellular senescence and apoptosis: how cellular responses might influence aging phenotypes.
      • Jeyapalan J.C.
      • Sedivy J.M.
      Cellular senescence and organismal aging.
      Senescent cells accumulate with age and at sites of age-related pathology.
      • Jeyapalan J.C.
      • Sedivy J.M.
      Cellular senescence and organismal aging.
      The senescent phenotype (eg, secretion of IL-6) may contribute to the proinflammatory state observed in normal aging that is exacerbated in frailty.

      Repair

      The repair cellular response involves removal of damaged proteins/lipids and organelles and recycling of constituent components via the catabolic/degradative machinery of cells—proteasomes, lysosomes, and autophagosomes.
      • Korolchuk V.I.
      • Menzies F.M.
      • Rubinsztein D.C.
      Mechanisms of cross-talk between the ubiquitin-proteasome and autophagy-lysosome systems.
      Proteasomes are large cellular protein complexes that degrade unnecessary or damaged proteins tagged with ubiquitin. Lysosomes are cellular organelles that fuse with vacuoles and dispense enzymes that degrade proteins, polysaccharides, nucleic acids, and lipids present in the vacuoles. Autophagosomes are involved in sequestering cytosolic components/organelles through phagophore formation, fusing the formed autophagosome with lysosomes, and degrading material by the lysosomal machinery (ie, autophagy). Normal cycling (flux) of these cellular catabolic vacuoles prevents the accumulation of damaged/aberrant molecular and cellular components.
      • Vellai T.
      • Takacs-Vellai K.
      • Sass M.
      • et al.
      The regulation of aging: does autophagy underlie longevity?.
      The removal and recycling phases of repair have gained considerable interest in research on aging. Conditions that modulate lifespan—mutations in the insulin/IGF-I signaling system, treatments that reduce the expression/activity of the transcription factor mammalian target of rapamycin (mTOR), and caloric restriction all increase autophagy.
      • Vellai T.
      • Takacs-Vellai K.
      • Sass M.
      • et al.
      The regulation of aging: does autophagy underlie longevity?.
      Aging cells exhibit an increase in mitochondrial DNA mutations and a decline in mitochondrial function.
      • Wallace D.C.
      A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine.
      Also, free radical generation by damaged mitochondria increases. Autophagy normally maintains homeostasis through mitochondrial turnover. Dysregulation of autophagy,
      • Cuervo A.M.
      • Bergamini E.
      • Brunk U.T.
      • et al.
      Autophagy and aging: the importance of maintaining “clean” cells.
      proteasomes,
      • Chondrogianni N.
      • Gonos E.S.
      Proteasome dysfunction in mammalian aging: steps and factors involved.
      and lysosomes
      • Chondrogianni N.
      • Fragoulis E.G.
      • Gonos E.S.
      Protein degradation during aging: the lysosome-, the calpain- and the proteasome-dependent cellular proteolytic systems.
      have all been observed with increasing age. Thus, functional capacity to remove oxidized, cross-linked, and/or unfolded proteins, nucleic acids, lipids, and polysaccharides is impaired, and these products increase with age. Lipofuscin (“aging pigment”) arises in lysosomes through the oxidation of unsaturated fatty acids through iron-generated free radicals. Lipofuscin is insoluble and refractile to cellular removal and recycling, accumulates with age, and may compromise organelle functional capacity by “overstuffing” organelles or diverting hydrolases and lipases away from their normal substrates.

      Systemic responses to stressors: inflammation

      Inflammation is a sentinel systemic response to stressors that plays a central role in the aging process in normal, healthy individuals.
      • Stout R.D.
      • Suttles J.
      Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes.
      The classic definition of inflammation refers to 5 cardinal signs: calor (heat), dolor (pain), rubor (redness), tumor (swelling), and functio laesa (loss of function). Inflammation modulates the cellular responses to stressors, and cellular responses can regulate components of the inflammatory response. Immunosenescence is the decline in the function of the adaptive immune system that occurs during aging that is associated with thymic involution, alterations in T-cell subsets, and reduction in antibody production. As adaptive immunity declines, innate immunity systems exhibit low-level but chronic activation that, with oxidative stress, leads to a low-level but chronic proinflammatory phenotype. A proinflammatory state may underlie several pathologies, including cancer,
      • Aggarwal B.B.
      • Shishodia S.
      • Sandur S.K.
      • et al.
      Inflammation and cancer: how hot is the link?.
      cardiovascular disease,
      • Osiecki H.
      The role of chronic inflammation in cardiovascular disease and its regulation by nutrients.
      • Diomedi M.
      • Leone G.
      • Renna A.
      The role of chronic infection and inflammation in the pathogenesis of cardiovascular and cerebrovascular disease.
      diabetes mellitus,
      • Duncan B.B.
      • Schmidt M.I.
      The epidemiology of low-grade chronic systemic inflammation and type 2 diabetes.
      osteoporosis,
      • Ginaldi L.
      • Di Benedetto M.C.
      • De Martinis M.
      Osteoporosis, inflammation and ageing.
      rheumatoid arthritis,
      • Wong S.H.
      • Lord J.M.
      Factors underlying chronic inflammation in rheumatoid arthritis.
      and cognitive disorders, such as Alzheimer and Parkinson disease.
      • McGeer P.L.
      • McGeer E.G.
      Inflammation and the degenerative diseases of aging.
      It is thought that these altered cytokines, in the local tissue microenvironment, perturb cellular functional capacity facilitating disease progression. “Inflammaging” is the term used to describe this proinflammatory state associated with aging,
      • Giunta S.
      Is inflammaging an auto[innate]immunity subclinical syndrome?.
      which has also been termed molecular inflammation.
      • Chung H.Y.
      • Kim H.J.
      • Kim K.W.
      • et al.
      Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction.
      • Chung H.Y.
      • Cesari M.
      • Anton S.
      • et al.
      Molecular inflammation: underpinnings of aging and age-related diseases.
      Several studies have shown significant association of elevated IL-6 levels with frailty in older adults.
      • Leng S.
      • Chaves P.
      • Koenig K.
      • et al.
      Serum interleukin-6 and hemoglobin as physiological correlates in the geriatric syndrome of frailty: a pilot study.
      • De Martinis M.
      • Franceschi C.
      • Monti D.
      • et al.
      Inflammation markers predicting frailty and mortality in the elderly.
      • Leng S.X.
      • Xue Q.L.
      • Tian J.
      • et al.
      Inflammation and frailty in older women.
      • Leng S.X.
      • Yang H.
      • Walston J.D.
      Decreased cell proliferation and altered cytokine production in frail older adults.
      • Hubbard R.E.
      • O’Mahony M.S.
      • Calver B.L.
      • et al.
      Nutrition, inflammation, and leptin levels in aging and frailty.
      The altered inflammatory state observed in frailty may contribute to several frailty-associated pathologies. For example, proinflammatory cytokines affect the growth hormone/IGF-I axis.
      • Johnson R.W.
      • Arkins S.
      • Dantzer R.
      • et al.
      Hormones, lymphohemopoietic cytokines and the neuroimmune axis.
      “Sickness behavior” (fatigue, malaise, loss of interest in social activities, difficulty concentrating, and changes in sleep patterns) is triggered by the production of proinflammatory cytokines by macrophages and other cells of the innate immune system in response to immune challenge.
      • Dantzer R.
      • Bluthe R.M.
      • Laye S.
      • et al.
      Cytokines and sickness behavior.
      The cytokine hypothesis of depression suggests that proinflammatory cytokines can act as neuromodulators—key factors in the (central) mediation of the behavioral, neuroendocrine, and neurochemical features of depressive disorders.
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      • Kim Y.K.
      Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression.
      • Schiepers O.J.
      • Wichers M.C.
      • Maes M.
      Cytokines and major depression.
      The central action of cytokines may also account for the hypothalamic-pituitary-adrenal (HPA) axial hyperactivity that is frequently observed in several age-related disorders, because proinflammatory cytokines disturb the negative feedback inhibition of circulating corticosteroids on the HPA axis.
      • Porter R.J.
      • Gallagher P.
      • O’Brien J.T.
      Effects of rapid tryptophan depletion on salivary cortisol in older people recovered from depression, and the healthy elderly.
      • Harbour J.W.
      • Dean D.C.
      Rb function in cell-cycle regulation and apoptosis.
      • Fridman J.S.
      • Lowe S.W.
      Control of apoptosis by p53.
      • Cardoso S.M.
      • Oliveira C.R.
      Inhibition of NF-kB renders cells more vulnerable to apoptosis induced by amyloid beta peptides.
      • Jagani Z.
      • Singh A.
      • Khosravi-Far R.
      FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis.
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      Involvement of Rel/nuclear factor-kappaB transcription factors in keratinocyte senescence.
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      Down-regulation of a forkhead transcription factor, FOXO3a, accelerates cellular senescence in human dermal fibroblasts.
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      • et al.
      Autophagy regulation by p53.
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      BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.
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      Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor.
      • Zheng S.J.
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      • Wang P.
      • et al.
      Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function.
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      • Hussain S.P.
      • et al.
      Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation.
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      • Firestein G.S.
      NF-kappaB: a key role in inflammatory diseases.
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      • et al.
      Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation.

      Cross talk between cellular responses and inflammation

      The tumor suppressors retinoblastoma protein (pRb), p53, and forkhead transcription factor (FOXO) are key modulators of apoptosis, senescence, and repair responses. The central transcription factor in inflammatory responses is nuclear factor kappaB (NF-κB). NF-κB also modulates apoptosis, senescence, and repair responses. The proteins p53, pRb, FOXO, and NF-κB are controlled by complex pathways involving upstream regulators, downstream effectors, and cytosolic inhibitors (for NF-κB) that regulate expression of other genes, modulate cell-cycle progression, and are crucial for allowing normal cells to sense and respond to apoptosis and senescence signals. These transcription factors have direct effects on increasing or decreasing cellular responses (Table 1).
      Table 1Cellular and systemic response regulation by key transcription factors
      Transcription Factor
      Responsep53RbNF-κBFOXO
       Apoptosis
      • Harbour J.W.
      • Dean D.C.
      Rb function in cell-cycle regulation and apoptosis.
      • Fridman J.S.
      • Lowe S.W.
      Control of apoptosis by p53.
      • Cardoso S.M.
      • Oliveira C.R.
      Inhibition of NF-kB renders cells more vulnerable to apoptosis induced by amyloid beta peptides.
      • Jagani Z.
      • Singh A.
      • Khosravi-Far R.
      FoxO tumor suppressors and BCR-ABL-induced leukemia: a matter of evasion of apoptosis.
       Senescence
      • Wesierska-Gadek J.
      • Ranftler C.
      • Schmid G.
      Physiological ageing: role of p53 and PARP-1 tumor suppressors in the regulation of terminal senescence.
      • Ohtani N.
      • Yamakoshi K.
      • Takahashi A.
      • et al.
      The p16INK4a-RB pathway: molecular link between cellular senescence and tumor suppression.
      • Bernard D.
      • Gosselin K.
      • Monte D.
      • et al.
      Involvement of Rel/nuclear factor-kappaB transcription factors in keratinocyte senescence.
      • Kyoung Kim H.
      • Kyoung Kim Y.
      • Song I.H.
      • et al.
      Down-regulation of a forkhead transcription factor, FOXO3a, accelerates cellular senescence in human dermal fibroblasts.
       Repair/autophagy
      • Maiuri M.C.
      • Galluzzi L.
      • Morselli E.
      • et al.
      Autophagy regulation by p53.
      • Tracy K.
      • Dibling B.C.
      • Spike B.T.
      • et al.
      BNIP3 is an RB/E2F target gene required for hypoxia-induced autophagy.
      • Copetti T.
      • Bertoli C.
      • Dalla E.
      • et al.
      p65/RelA modulates BECN1 transcription and autophagy.
      • Zhao J.
      • Brault J.J.
      • Schild A.
      • et al.
      Coordinate activation of autophagy and the proteasome pathway by FoxO transcription factor.
       Inflammation
      • Zheng S.J.
      • Lamhamedi-Cherradi S.E.
      • Wang P.
      • et al.
      Tumor suppressor p53 inhibits autoimmune inflammation and macrophage function.
      • Ying L.
      • Marino J.
      • Hussain S.P.
      • et al.
      Chronic inflammation promotes retinoblastoma protein hyperphosphorylation and E2F1 activation.
      • Tak P.P.
      • Firestein G.S.
      NF-kappaB: a key role in inflammatory diseases.
      • Snoeks L.
      • Weber C.R.
      • Wasland K.
      • et al.
      Tumor suppressor FOXO3 participates in the regulation of intestinal inflammation.
      The induction (↑) or repression (↓) of cellular and systemic responses by key transcription factors and the references supporting that assessment are given in parenthesis.
      Interaction between p53 and pRb is well known in their role in determining whether DNA damage can be repaired or whether apoptosis should occur.
      • Hooper M.L.
      The role of the p53 and Rb-1 genes in cancer, development and apoptosis.
      Cross talk also occurs between p53 and FOXO
      • You H.
      • Mak T.W.
      Crosstalk between p53 and FOXO transcription factors.
      and pRb and NF-κB.
      • Kim Y.A.
      • Lee W.H.
      • Choi T.H.
      • et al.
      Involvement of p21WAF1/CIP1, pRB, Bax and NF-kappaB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells.
      The communication between response regulators can be multileveled. For example, p53 acts in at least 2 stages of inflammation—as a general inhibitor of NF-κB-dependent transcription and, through an unknown mechanism, as a positive regulator of neutrophil clearance by macrophages.
      • Zhou M.
      • Gu L.
      • Zhu N.
      • et al.
      Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: interaction of IkBm and p53.

      Summary

      The cellular responses of apoptosis, senescence, and repair and the systemic response of immune activation/inflammation have evolving roles in contributing to the aging phenotype. Homeostatic mechanisms effect change through these responses; thus, they are likely candidates for pathways that may contribute to the failure in homeodynamics seen in frailty. Dysregulation of apoptosis may contribute to the frailty traits of sarcopenia and weakness. Similarly, the cellular senescent phenotype, secreting proinflammatory cytokines, may contribute to the dysregulated inflammatory state seen in frailty. One can further speculate that deficits in repair in specific tissues (eg, muscle, nerves, bone) contribute to frailty. Facets of senescence, apoptosis, and repair response have yet to be carefully studied in the setting of frailty. It may be expected that the patterns observed in normal aging between these different cellular and systemic responses would be further perturbed or accelerated in the syndrome of frailty. Future investigations targeting these areas will provide the data necessary to test these hypotheses related to the biology of aging.

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