Evolutionary senescence

The earliest theories of aging and death held that limited lifespan creates room for upcoming generations, therefore helping the species as a whole. This would also allow natural selection for the fittest individuals to occur faster, with more individuals being born per unit of time. However, in nature, mortality usually has little to do with aging, and is more commonly associated with environmental, or extrinsic, factors, such as predation, infectious disease, or starvation.[4] An evolutionary theory of aging rose from the work of J. B. S. Haldane, Peter Medawar, and George Williams, based on the idea that natural selection acts at an individual level, not a species level, and that only genes involved in survival and health preceding the reproductive period would be acted upon by natural selection.[5] There is less need to maintain integrity of processes such as macromolecular repair and tight control of molecular pathways as organisms progress beyond sexual maturity, when the fitness of the organism is no longer evolutionarily relevant. Therefore natural selection’s effects would decline with age, and mutations that are deleterious in older age will be passed on before they are able to negatively affect the organism. Later in life these deleterious mutations would give rise to aging phenotypes. This became known as the mutation accumulation theory.

A related theory, that of antagonistic pleiotropy, states that genes responsible for aging processes may not have been passively allowed, as in the mutation accumulation theory, but that they may have actually undergone positive selection due to some benefit they confer to individuals in early life.[5] These benefits would outweigh deleterious pro-aging effects past reproductive age, which are less subject to evolutionary pressures. Cellular senescence, which will be discussed later in the chapter, is considered to be an example of antagonistic pleiotropy because it defends against malignancy in early life but contributes to disease and tissue dysfunction later in life.

A third evolutionary theory of aging is that of the disposable soma, proposed by Thomas Kirkwood.[6, 7] Because an organism has a finite amount of resources and energy, it must choose to allocate them among the processes of growth, repair, and reproduction. Enough resources must be allocated to repair in order to prevent what has been called “error catastrophe,” or the accumulation of so many units of damage or error that the organism can no longer survive.[8] However, some basal level of error must be allowed because energy must be allocated to the essential processes of reproduction and metabolism. It follows that species threatened by predation should allocate more energy to reaching reproductive capacity rather than repairing damage, and may thus have an increased rate of aging. Therefore, safer environments should favor a reduced rate of aging, and organisms that reproduce later in life should have a reduced rate of aging, since selective pressure would persist longer into the lifespan.

Programmed aging

The programmed aging theory rejects the possibility that aging is a stochastic process of wear and tear on an organism, and suggests that aging is programmed just as development is. Subsets of this theory propose genetic, hormonal, or immunologic control of aging and longevity.

The idea that genes evolved to modulate longevity has been mostly discounted based on the idea that natural selection has most of its effects before the reproductive stage of life. However, it is plausible that certain gene variants may confer lifespan advantages, or that gene expression may change to favor deleterious processes later in life. Many pathways have been implicated in a genetic basis for aging in model systems such as yeast and the nematode C. elegans, most notably the growth hormone/insulin-like growth factor (IGF-1) pathway, as will be discussed.[9] In humans, the link between genetics and a long and healthy life is more elusive, although familial clustering of longevity has been reported.[10, 11] Many studies of centenarians hinge on the idea that genes having increased prevalence with age should confer benefits to lifespan. Several variants have been identified that seem to correlate with longer life – for example variants in the apolipoprotein E (APO-E) and IGF-1 signaling pathways – but these studies have yet to find a smoking gun for the longevity phenotype.

Hormones modulate metabolic activity and insulin sensitivity regulate oxidative stress, drive maturation, and direct processes such as bone formation and remodeling that have huge impacts on organismal health.[12] Thus, there is much interest in the possibility that hormones influence aging by a sort of biological clock, and that changes in hormone levels over the lifespan cause age-related phenotypes. The longest-lived mouse is the Ames dwarf mouse, which has a 70% greater maximum lifespan than nonmutant mice.[13] These dwarf mice are deficient in growth hormone as well as prolactin and thyroid-stimulating hormone. Growth hormone receptor knockout mice also have increased maximum lifespan [14] as do other vertebrates and invertebrate species with reduced growth hormone/IGF-1 action. Interestingly, humans with Laron dwarfism lacking the growth hormone receptor have essentially no risk of diabetes or cancer, even in old age.[15] Female children of centenarians with an IGF receptor mutation, in addition to having a longer life expectancy than their spouses, have shorter stature than their spouses.[16] Furthermore, smaller individuals within a species live longer on average than larger members (e.g., small versus large dogs). This, in turn, has been linked to reduced growth hormone/IGF-1 signaling.[17]

The immunosenescence theory of aging points to a decline in immunity with age that can cause increased susceptibility to infection and therefore increased mortality. Immune cells, in addition to having a limited replication capacity, undergo a decline in function in aging organisms – for example, decreased activation potential of T cells in older individuals.[18] In addition, it has been proposed that anti-inflammatory pathways may also decline in function with age, allowing the development of a chronic, low-grade sterile inflammatory state that causes tissue damage. This imbalance between pro- and anti-inflammatory pathways has been termed “inflammaging.”[19]

Somatic inevitability

The somatic inevitability theory, also known as the wear-and-tear theory, addresses the practical concern that organisms simply cannot have normal function indefinitely, due to environmental and metabolic damage as well as a limit to regenerative mechanisms. Aging is therefore an accumulation of damage and an exhaustion of regenerative potential.

One version of this theory is called the rate-of-living hypothesis, which is based on the work of Max Rubner and Raymond Pearl and postulates that lifespan should have an inverse relationship to metabolic rate. Denham Harman later linked this theory to free radicals and oxidative stress.[20] However, it has since been determined that the rate of living of an organism cannot alone account for its lifespan potential. For example, naked mole rats and mice are approximately the same size, and although naked mole rats have a tenfold longer lifespan than mice, they have an increased metabolic rate and free radical generation compared to mice.[21] Other components of the wear-and-tear theory are the cross-linking theory, in which the accumulation of protein cross-links and glycation of macromolecules slow down metabolic processes and cause age-related dysfunction, and the DNA damage theory, in which accumulated DNA damage during the lifespan causes cellular and mitochondrial dysfunction that lead to age-related pathology.

Chronic, “sterile” inflammation

Low-level, chronic inflammation is detected in many tissues with increasing age and is associated with age-related disease states such as diabetes, Alzheimer’s disease, sarcopenia, and atherosclerosis.[19] Age-related sterile inflammation is frequently associated with the infiltration of immune cells as well as the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and interleukin 8 (IL-8). This chronic inflammation is known as sterile inflammation due to the lack of detectable pathogens or the characteristic redness, pain, heat, or swelling seen in local, acute inflammation. The source of this chronic inflammation has not been well defined, although candidate sources include diminished regulation of the immune system, oxidative stress, chronic antigenic stress, and senescent cell accumulation.[19, 22]

In humans, the inflammatory factors IL-6 and C-reactive protein have been implicated as predictors of mortality, independent of age, sex, body mass index (BMI), smoking status, diabetes, or cardiovascular disease.[23] IL-6 alone has been shown to be a correlate of frailty and a predictor of functional disability in older adults.[24, 25] With enough evidence and reliable measurement strategies, immunologic biomarkers may help us to predict which individuals are more likely to experience disability, frailty, or morbidity in the near future. This could allow preventative measures to be taken before the onset of disease or disability, and perhaps these biomarkers can even be used to follow response to interventions.

Cellular senescence

Cellular senescence is an essentially irreversible growth arrest that can be triggered by a host of stimuli – including but not limited to oncogene activation, oxidative stress, metabolic stress, and telomere erosion – that evolved as a defense against tumor formation. Cells that undergo senescence adopt a characteristic enlarged shape, accumulate tumor suppressor proteins such as p21 and p16, exhibit a senescence-associated increase in beta galactosidase activity, and begin to secrete a variety of growth factors, cytokines, and matrix remodeling factors, collectively termed the senescence-associated secretory phenotype (SASP).[26] Often cited as an example of antagonistic pleiotropy, senescent cells protect organisms against malignancy in early life but can have detrimental effects as they accumulate in tissues with age, paradoxically including the promotion of pro-tumor environments.[27]

The burden of senescent cells in human skin correlates with age.[28] They also accumulate in adipose tissue with advancing age in wild-type mice, but at a slower rate in long-lived Ames and growth hormone receptor deficient mice.[29] Cellular senescence and the resulting SASP are thought to produce a chronic, low-level inflammatory state in the body and have been implicated in a variety of age-related pathologies.[27, 30] Recent work in genetic mouse models allowing clearance of senescent cells has established a causal link between cellular senescence and age-related disease by showing that removal of senescent cells from progeroid mice can extend healthspan and delay age-related phenotypes, such as subcutaneous fat tissue loss, cataract formation, and sarcopenia. In addition, senescent cell removal later in life stalled progression of age-related pathology, even after it had emerged.[31] These studies support a causal link of senescent cells to age-related disease pathologies and establish senescent cells and their secretory phenotype as promising targets for developing agents to delay, prevent, ameliorate, or treat age-related diseases and dysfunction.[22]

Macromolecular dysfunction

At the most fundamental level, aging has profound effects on macromolecules, including protein, DNA, RNA, and lipids. These changes can fall into two categories: processes that decline or become defective with age, such as DNA damage repair or autophagy, or processes that are less common early in life but which occur more frequently with age, such as advanced glycation end product formation and lipotoxicity.

Organisms acquire genomic damage over time through exposure to the environment and metabolic byproducts, and they require the action of DNA repair mechanisms to deal with these insults. Accordingly, a positive correlation between DNA repair and longevity has been shown, as well as premature aging phenotypes in mice with genetic ablation of genome repair mechanisms.[32] Accumulation of mitochondrial DNA damage, thought to be mainly caused by reactive oxygen species (ROS), could cause mitochondrial dysfunction with age, leading to less efficient adenosine triphosphate (ATP) production. This age-related mitochondrial dysfunction might play a major role in cardiovascular, metabolic, skeletal, and other age-related pathologies.[33] Other levels of genetic regulation can also be compromised with aging (e.g., at the level of noncoding RNA). Dysregulation of cellular processes can occur in part because of an age-related decline in Dicer protein, which processes microRNA.[34]

Alteration of proteins, including increased glycation, oxidation, and cross-linking, paired with reduced turnover of proteins, or autophagy, can cause cellular dysfunction and protein aggregation with age. Aggregation of proteins is known to play a role in many diseases, such as Alzheimer’s, Parkinson’s, insulin-dependent diabetes, dilated cardiomyopathy, and glomerulosclerosis.[35] Rates of autophagy decline with age, and conversely, genetic inhibition of autophagy mimics aging pathology.[36]

In addition to proteins, glycation can affect phospholipids and nucleic acids to form what are known as advanced glycation end products (AGEs). With age, defenses against the formation of these glycation adducts is reduced. AGEs can activate to pro-inflammatory signaling cascades by input through a cell surface receptor-mediated mechanism (RAGE).[37] AGEs are known to accumulate in normal aging brains, but have also been implicated in cultured neuron toxicity as well as amyloid beta (Aβ) aggregation.[38, 39] AGEs have been implicated in the pathogenesis of diabetes and its complications.[40]

With age, even lean individuals acquire ectopic lipid deposition in non-adipose tissues such as muscle, liver, and pancreatic beta cells. This can lead to lipotoxicity, which contributes to metabolic dysfunction, especially in the setting of overnutrition.[41] Defenses against lipotoxicity at both the cellular and organismal level are also blunted with age, exacerbating lipotoxic effects on tissues.[42, 43]

In sum, the accumulation of damage paired with a loss of regulatory mechanisms causes increased stochasticity with age, which results in tissue dysfunction and disease. Because the repair and regulatory mechanisms that control these processes are so fundamental, and because their failure with age is implicated in many age-related diseases, these mechanisms represent possible targets for the development of clinical interventions with potentially transformative impact.

Progenitor cell function decline

Stem cell and progenitor pools are not unlimited and may become depleted with age and increased need for tissue repair. In addition, intrinsic stem cell function declines with age. Aged stem cells may fail to self-renew, fail to respond to growth and differentiation signals in their environment, or may undergo senescence.[44] Even if they are able to differentiate, stem cells may produce a skewed population of progeny cells – for example, a skew toward the myeloid lineage with age in the context of the hematopoietic system.[45]

The aging microenvironment, both local and systemic, also plays a large role in the dysfunction of stem cells with aging. The chronic, sterile inflammation of aging may contribute to a toxic or suppressive environment that does not allow proper stem cell function. In addition, crosstalk between organ systems – for example, between adipose tissue and bone – is known to affect progenitor cell function and could serve as a mechanism for the propagation of aging signals.[46] Heterochronic parabiosis experiments, in which an experimental animal is exposed to the systemic circulation of a separate animal, have shown that exposure to a young circulating environment can rejuvenate stem cells from aging animals.[47] This suggests that aging progenitor cells may have at least some preservation of function, but their replicative capacity is suppressed by the aging microenvironment.

Centenarians

At the 2010 census, there were 1.74 centenarians for every 10,000 people in the United States. Notably, those individuals living more than 100 years often experience a “compression of morbidity,” developing cancer, heart disease, and other common ailments much later in life than the population at large.[48, 49] This effect becomes more apparent in supercentenarians, or those living more than 110 years, exemplified in a 2012 study classifying 69% of people older than 110 as “escapers” who had experienced onset of only one age-related disease after the age of 100.[50]

There has been a longstanding interest in determining characteristics that differentiate centenarians from the general population. Genome-wide association studies have been conducted to compare the genetic makeup of centenarians’ children with the spouses of those children, presumably not descendants of centenarians. These studies have struggled to find strong correlations between any single nucleotide polymorphism and exceptional lifespan.[51] A 1994 study found that ApoE4 mutations predisposing to atherosclerosis were less common in centenarians as compared to a general population of age 20 to 70.[52] Polymorphisms in insulin signaling pathway genes (e.g., FOXO3A) have also been implicated in human longevity, consistent with work showing that inhibition of insulin signaling extends lifespan in C. elegans and mice.[53–55]

Premature aging in HIV patients and survivors of childhood cancers

Treatments that prolong life in patients with human immunodeficiency virus (HIV) and cancer have recently been implicated in premature aging. Patients with HIV, even well controlled, seem to develop age-related diseases prematurely. This may be partially due to residual infection, coinfection (e.g., viral hepatitis), and chronic activation of the immune system that leads to exhaustion of immune cells and inflammation. However, antiretroviral (HAART) therapy has also been implicated as a source of oxidative and mitochondrial damage that may contribute to premature aging, and has been linked to dysfunction of multiple organ systems as well as increased deposition of Tau protein, a neurodegenerative marker.[56]

Individuals who underwent treatment for childhood cancers are another population in which premature aging syndrome has been observed. Frailty phenotypes have been found to be more prevalent in survivors of childhood cancer, especially in females, compared to an age-matched control group.[57] These individuals have also started to show early incidence of diseases such as coronary artery disease, which are normally associated with aging and therefore not usually screened for until later in life.[58] These findings have implications for the long-term care of this emerging cohort, which continues to be rigorously studied.

Gender differences in longevity

It has long been observed that human females have a longer life expectancy than males. Eighty-two percent of centenarians in the 2010 census were female.[59] As noted earlier, pharmacologic lifespan extension strategies in basic research have shown differential effects on male and female experimental animals, as do some single gene mutations such as IGF-1 receptor deficiency. These observations introduce a new wrinkle into aging research by suggesting that lifespan- or healthspan-extending strategies may not have similar effects in males and females. On the other hand, this observation presents an opportunity. If we can discover the pathways responsible for greater female longevity, we may be able to target that pathway pharmacologically to the benefit of both older men and women.