Cellular Mechanisms of Aging

Introduction

Aging changes are universal within a species and are intrinsic and progressive. They are universal; each true aging change should develop in all individuals in a species if they live long enough. Aging is intrinsic because these changes occur despite environmental cues, although the environment can alter their timing. The term progressive refers to the time dependency of aging processes. After adulthood, aging is associated with a general decline in cellular, tissue, and systemic function, loss of reproductive capacity, decreased resilience, and the ability to adapt to environmental perturbations and respond effectively to disease. Age-related phenotypes or diseases (e.g., development of certain cancers, such as prostate cancer, or onset of atherosclerosis) are likely predisposed to by fundamental aging processes that are operative during particular stages of life. These age-related phenotypes and diseases are heterogeneous and, unlike true aging changes, are not universal, occurring segmentally in different tissues and appearing at different times among individuals.

Recent important advances have been made in our understanding of the basic biology of aging. These insights into the cellular and molecular biology of aging have led to development of a number of interventions, both lifestyle and drugs, that extend life span and health span—the period during life free of chronic disease, pain, disability, and dependency—at least in mice. If these can be translated into humans, such interventions may prove to delay, prevent, alleviate, or even reverse the age-related diseases and disabilities that are the leading drivers of morbidity, mortality, and health expenditures in developed and developing societies. These age-related conditions include atherosclerosis, most cancers, mild cognitive impairment, dementias, Parkinson and other neurodegenerative diseases, type 2 diabetes, renal dysfunction, arthritis, blindness, frailty, and sarcopenia. For each condition, chronologic aging is a major risk factor. Indeed, for most, aging is a larger risk factor than all others combined. Importantly, the major age-related diseases share the disturbances in tissue, cellular, and molecular function that also occur with chronologic aging. These include chronic sterile inflammation, cellular senescence, macromolecular damage (DNA, proteins, carbohydrates, and lipids), and stem and progenitor cell dysfunction. Based on these points, the geroscience hypothesis has been proposed: by targeting fundamental aging processes, it may be feasible to treat the major age-related chronic diseases and geriatric syndromes as a group, instead of one at a time. This hypothesis is being actively tested in experimental animal models and human cells. If true, and if the interventions that appear to be effective in targeting fundamental aging mechanisms in mice can be translated into humans, geriatrics practice and all of medicine as we know it could be transformed.

The basic biology of aging field has moved from an era of descriptive research to hypothesis-driven research, with a focus on elucidating mechanisms and, most recently, into developing interventions that target fundamental aging processes. The next phase, which has already started, is to translate these interventions into clinical application. Modulators and interventions that delay age-related changes in experimental animals include caloric restriction, several hundred single-gene mutations across species and, most recently several drugs. The single-gene mutations that extend life span or health span involve the growth hormone (GH)–insulin-like growth factor-1 (IGF-1)–insulin signaling pathway and other pathways related to anabolism and caloric restriction, as well as inflammation, the renin-angiotensin system, and cellular senescence, among others. In general, these genetic and pharmacologic interventions are related to inflammation, cell survival, cellular senescence, macromolecular processing, fuel and metabolic sensing and processing, caloric restriction, and stem and progenitor cell function. These interlinked processes, which appear to be the most likely targets for future clinical interventions to delay age-related dysfunction and chronic diseases as a group, are considered in this chapter.

Inflammation

A general decline in immunity occurs with aging, with increased susceptibility to infections, cancers, autoimmune disorders, and associated mortality. Immune cells undergo declines in function in aging organisms—for example, there is decreased macrophage function and impaired activation potential of T cells in older individuals. Additionally, the function of antiinflammatory pathways may also decline with aging, predisposing to development of a chronic, low-grade sterile inflammatory state that leads to tissue damage. The imbalance between proinflammatory and antiinflammatory pathways with aging has been termed inflammaging .

Chronic, low-level, nonmicrobial (or sterile) inflammation develops in multiple tissues with both aging and age-related chronic diseases. The source of this age-related chronic inflammation has not been pinpointed precisely. Candidate mechanisms include dysregulation of the immune system, chronic antigenic stimulation (e.g., by latent viruses), oxidative stress, increases in dysfunctional macromolecules (e.g., unfolded or aggregated proteins, glycation end products, or reactive lipids), and accumulation of senescent cells (see later). Chronic inflammation can drive tissue dysfunction by at least two mechanisms. First, infiltrating immune cells can degrade tissues because they release reactive or toxic moieties. Second, inflammatory cytokines can provoke phenotypic changes in nearby cells that are independent of the immune system. For example, interleukin (IL)-6 and IL-8 can stimulate angiogenesis, disrupt cell-cell communication, impede macrophage function, induce innate immune responses, and promote epithelial and endothelial cell migration and invasion. Furthermore, increases in tissue inflammation under basal conditions may contribute to an increase in susceptibility to autoimmune diseases, as well as to a restricted capacity to boost the extent of inflammation further when needed. This restriction in the dynamic range of inflammatory and cellular stress responses likely constrains the capacity to respond appropriately to infection, immunization, or injury.

Increases in inflammatory mediators, including elevated IL-6, tumor necrosis factor-α (TNF-α), and immune cell chemokine levels, are associated with multiple age-related diseases, including dementias, depression, atherosclerosis, cancers, and diabetes, as well as mortality. Sterile inflammation is perhaps the most important physiologic correlate of the age-related frailty syndrome that encompasses heightened vulnerability to stresses (e.g., surgery, infection, trauma), muscle wasting (sarcopenia), cachexia, and adipose tissue loss. Frailty predisposes to chronic disease, loss of independence, and mortality, as well as increased health costs.

Cellular Senescence

Cellular senescence refers to the essentially irreversible cell cycle arrest caused by potentially oncogenic and metabolic insults that evolved as a defense against tumor formation. Senescent cells adopt a characteristic enlarged shape, increased protein content, elevated tumor suppressor proteins such as p21 ^CIP1 and p16 ^INH4A , an increase in senescence-associated β-galactosidase activity, and elevated secretion of a number of growth factors, cytokines, immune cell–attracting chemokines, and matrix remodeling factors, collectively termed the senescence-associated secretory phenotype (SASP) or senescence-messaging secretome .

A number of inducers, including oncogene activation, DNA damage, telomere erosion, oncogenic proteins, fatty acids, oxidative stress, mitogens, cytokines, and metabolites, can act alone or in combination to push cells into the senescent cell fate through pathways involving p16 ^INK4A /Rb (retinoblastoma), p53/p21 ^CIP1 , and probably others. These contribute to the widespread changes in gene expression and chromatin remodeling (heterochromatin formation) that underlie senescence-associated growth arrest and changes in morphology. In these respects, cellular senescence can be viewed as a cell fate reminiscent of differentiation, replication, or apoptosis, with external and internal cues leading to activation of transcription factor cascades, gene expression changes, chromatin remodeling, and changes in function. Intracellular autocrine loops, including loops involving interleukins and reactive oxygen species (ROS), reinforce the progression to altered gene expression, irreversible replicative arrest, and heterochromatin formation over a matter of days to weeks.

Cellular senescence contributes to age-related dysfunction and frailty and is frequently operative at sites of pathology underlying chronic age-related diseases. Senescence can occur at any point during life, even in blastocysts and the placenta. Indeed, senescence is important in remodeling during embryogenesis. Even though senescent cells are resistant to cell death through apoptosis, they are normally removed by the immune system in younger individuals. However, senescent cells accumulate in multiple tissues with advancing age. Senescent cell burden is, in turn, associated with life span. At 18 months of age, long-lived Ames dwarf, Snell dwarf, and GH receptor knockout mice have fewer senescent cells in their adipose tissue than age-matched control wild-type animals, whereas short-lived GH overexpressing mice have more. Caloric restriction sufficient to increase life span in mice is associated with decreased expression of p16 ^INK4A , a senescence marker, in multiple tissues compared to animals fed ad lib. Conversely, senescent cells accumulate in fat and other tissues in obese animals and humans, especially when accompanied by diabetes. Consistent with the geroscience hypothesis, obesity and diabetes are associated with an accelerated onset of other aging- and senescence-associated conditions, including atherosclerosis, vascular dysfunction, sarcopenia, cognitive impairment, dementia, early menopause, and cancers, including non–hormone-dependent cancers. Progeroid mice, such as mouse models of Werner and Hutchinson-Guilford progerias, as well as Klotho -deficient, Ercc ^−/− , and BubR1 ^H/H mice, have increased numbers of senescent cells. In comparisons across longer versus shorter lived mouse cohorts, senescent cell accumulation in liver and intestinal crypts predicted mean and maximum life spans.

The SASP involves the release of proinflammatory cytokines, chemokines, prothrombotic factors, and extracellular matrix proteases that cause tissue damage, as well as extracellular matrix proteins that can contribute to dysfunctional tissue architecture. In addition to removing cells from the progenitor–stem cell pool, senescence may contribute to tissue dysfunction and chronic disease predisposition through the SASP and the chronic sterile inflammation and extracellular matrix disorganization that it causes. The associations among cellular senescence, aging, and age-related pathologies prompted testing if senescent cell clearance ameliorated dysfunction. Genetically targeting senescent cells in progeroid mice that expressed a drug-activatable so-called suicide gene only in senescent cells enhanced health span. Even clearing only around 30% of senescent cells from these mice led to partial reversal of age-related lipodystrophy and decreased progression of frailty, sarcopenia, and cataract formation.

Furthermore, senescent cell removal later in life delayed progression of age-related pathology, even after it had emerged. Drugs that selectively eliminate senescent cells—senolytic drugs— have been discovered. These drugs alleviate age-related cardiac and carotid vascular dysfunction in old mice, radiation-induced muscle dysfunction in younger mice, and neurologic dysfunction, osteoporosis, and frailty in progeroid mice. Cellular senescence is associated with many of the chronic diseases and disabilities that are leading drivers of morbidity, mortality, and health costs. Senescent cells have been identified at sites of pathology in a number of these conditions and may have systemic effects that predispose to others ( Table 9-1 ). These findings support a link between senescent cells and age-related dysfunction. There is now the prospect that drugs that target senescent cells and the SASP might come into clinical use to delay, prevent, ameliorate, or even reverse age- and senescence-related dysfunction and diseases in humans.

Macromolecular Dysfunction

Aging is associated with the accumulation of damaged macromolecules, including DNA, proteins, carbohydrates, and lipids in and around cells. In most cases, these damaged macromolecules or the processes underlying their accumulation are related to chronic inflammation, cellular senescence, and stem and progenitor cell dysfunction, as well as to the major age-related chronic diseases. As considered later, many of the drugs that show promise for enhancing health or life span act on processes responsible for the generation or effects of these damaged macromolecules.