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Division of Geriatric Medicine and Gerontology, Department of Medicine, Johns Hopkins University School of Medicine, Johns Hopkins University, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
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
Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
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.
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.
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.
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.
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
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.
Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
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.
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 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).
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,
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.
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.
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,
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.
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
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,
and telomere-independent pathways, which include cytoskeletal, interferon-related, IGF-related, mitogen-activated protein kinase, and oxidative stress pathways.
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.
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.
The contribution of cellular (replicative) senescence to organismal aging has been controversial, although increasingly; evidence seems to link cellular senescence to 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.
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.
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.
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.
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,
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,
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.
“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.
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.
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.
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
The induction (↑) or repression (↓) of cellular and systemic responses by key transcription factors and the references supporting that assessment are given in parenthesis.
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.
Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: interaction of IkBm and p53.
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.
References
Fried L.P.
Tangen C.M.
Walston J.
et al.
Frailty in older adults: evidence for a phenotype.
Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study.
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.
Associations of neutrophil and monocyte counts with frailty in community-dwelling disabled older women: results from the Women’s Health and Aging Studies I.
Transfection of a dominant-negative mutant NF-kB inhibitor (IkBm) represses p53-dependent apoptosis in acute lymphoblastic leukemia cells: interaction of IkBm and p53.
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