Immunosenescence and Inflammaging in Dogs and Cats: A Narrative Review

ABSTRACT

A consistent and important feature of biological aging is the change in the types and functions of cells comprising the immune system. Across various mammalian species, this change follows consistent patterns, including diminished protective capacity, leading to increased vulnerability to infectious disease, and increased low‐grade chronic inflammation, raising the risk of numerous aging‐associated diseases. Although these patterns are well characterized in rodents and humans, there is less evidence available in companion animal species. The most recent review of the literature evaluating aging changes in the immune system in dogs and cats was published in 2010. The purpose of this narrative review is to summarize the currently available information concerning immune system aging in these species and to review what is known about the clinical consequences of this process and about potential strategies for mitigation.

Abbreviations

CRP

C‐reactive protein

IL

interleukin

LPS

lipopolysaccharide

mRNA

messenger ribonucleic acid

NK

natural killer

SASP

senescence‐associated secretory phenotype

TGF

transforming growth factor

TNF

tumor necrosis factor

1. Introduction

Immunosenescence and inflammaging are changes in immune system cell types and functions that occur with aging. Figure 1 illustrates the characteristic patterns of immunosenescence and inflammaging.

FIGURE 1.

Patterns of change with immunosenescence in the innate and adaptive immune systems and with inflammaging as seen in humans, dogs, and cats.

In general, immunosenescence involves the following elements:

• Diminished ability to respond to novel challenges, including infectious agents, parasitic organisms, and neoplastic cells

• Diminished ability to generate protective immunity in response to vaccination, though this is variable and inconsistent between studies

• Diminished memory response to previously encountered or latent challenges, though this is typically better preserved than the response to novel challenges

• Relative decrease in naïve and increase in differentiated immune cell types

• Relatively greater impairment of the adaptive immune system than the innate immune system

• Relative increase in pro‐inflammatory cell types and signaling and decrease in anti‐inflammatory and regulatory cell types and activity

• Increased accumulation of senescent cells with a senescence‐associated secretory phenotype (SASP)

• An overall decrease in proliferative capacity, including diminished bone marrow and stem cell function, predominantly in the lymphoid lineage

Most research characterizing these processes has been done in humans and rodents. There is, however, considerable similarity in the effect of aging on the immune system across mammalian species, and there is also some direct research evidence characterizing immunosenescence in companion animals, including dogs and cats. This field is highly dynamic, with new information about the underlying mechanisms and the clinical consequences of these processes appearing regularly.

The most recent comprehensive review of immunosenescence and inflammaging research in dogs and cats was published in 2010 [1]. Some discussions of canine aging in general have touched on these topics but have not assessed the most recent literature in detail [2, 3, 4]. The goal of the current review is to summarize the current understanding of immunosenescence and inflammaging, identify important knowledge gaps, and consider potential strategies for mitigating the negative consequences of these changes in companion cats and dogs.

2. Immunosenescence

Immunosenescence refers to the multitude of impairments that occur in the immune system as organisms' age [1, 5]. These include changes in immune cell number, subtype, and function in both the innate and adaptive immune systems. Immunosenescence also involves changes that contribute to the phenomenon of inflammaging: chronic low‐grade inflammation resulting from an imbalance between pro‐ and anti‐inflammatory cellular activity, including alterations in intercellular signaling and increased numbers of senescent immune cells exhibiting SASP.

The consequences of immunosenescence and inflammaging include reduced protection against infection and, paradoxically, an increased risk of autoimmunity. These processes also raise the risk of neoplasia and many other aging‐associated diseases, and they contribute to frailty and diminished quality of life in geriatric individuals [6].

There is extensive individual variation in the extent and expression of immunosenescence and inflammaging, driven by differences in genotype and by numerous environmental exposures that modulate immune function [5, 7, 8]. Some specific genes have been identified that influence susceptibility to aging‐associated changes in immune function and the balance of mechanisms promoting and inhibiting inflammation, and these partially explain individual differences in immune system health and inflammaging during aging [9].

Chronic stimulation of the immune system, by infectious organisms and other factors, also modulates immunosenescence, and differences in such environmental factors can influence the severity of age‐related changes in immune function and inflammaging [10, 11]. This implies that immunosenescence, such as aging generally, is a potentially modifiable risk factor for morbidity and mortality. An understanding of the detailed mechanisms underlying changes in immune function with age can inform interventions to preserve health and slow inflammaging and immunosenescence.

The term immunosenescence was coined by Roy Walford [12] in 1969 in his elaboration of the immunologic theory of aging, which attributed the deleterious effects of aging to a form of autoimmunity. Although this explanation of aging has been superseded by more multifactorial models [13], Walford's work stimulated a greater appreciation of the role of the immune system in aging. Current theory recognizes intricate and reciprocal connections between multiple hallmarks of aging and the immune system, with immunosenescence and inflammaging being both consequences and drivers of change in other systems [2, 13].

3. Inflammaging

Inflammaging is a more recent term, introduced in 2000 [14]. Inflammation is a core feature of the immune system, and it serves a critical purpose in defending against infectious and parasitic organisms and promoting wound healing [15]. However, persistent inflammation can be deleterious, and with aging the balance between mechanisms promoting and inhibiting the inflammatory response is disrupted. This leads to a state of chronic, low‐grade inflammation that impairs immune function and increases the risk of multiple aging‐related diseases. Inflammaging is a feature of immunosenescence, resulting from changes in the number, subtype, and functioning of cell lines in both the innate and adaptive immune systems.

4. Causes of Immunosenescence and Inflammaging

The causes of immunosenescence and inflammaging are complex and incompletely understood. In the context of natural selection, it is possible that declining immune function might be an adaptive response to the shifting balance of benefits and risks from immune system activity over the life cycle [5, 16]. Exposure to novel pathogens and parasites is typically greatest early in life, and in this phase the immune system is robust and primed to aggressively identify and combat novel threats. The risk of a deleteriously excessive or misdirected immune response would likely be less than the risk of external infectious and parasitic agents in young animals.

However, before the relatively recent advent of rapid long‐distance transportation, most animals lived in constant geographic and social environments, meaning relatively little variation in the infectious and parasitic threats they were exposed to. Effective recognition and response to familiar threats would be most important as individuals aged, in this context. Preserving a robust ability to respond to novel threats in older animals would be less important.

This would explain the potential adaptive value of having a greater proportion of differentiated memory, rather than naive cell types prepared to react to novel threats, as individuals age. It would also explain the general decrease in immune function with age. The risk of an inadequate response to novel threats would become lower than the risk of deleterious autoimmunity, which would likely increase with time if the overall potency of the immune response did not diminish.

Under the theory of antagonistic pleiotropy [17], the benefits of a robust immune system in early life would be great enough to outweigh the potential harms in older individuals, especially when few lived to the geriatric stage. Other theories have been advanced to explain immunosenescence and inflammaging in an evolutionary context, and there are multiple plausible but not conclusive potential explanations [18, 19].

Many proximate causal mechanisms have been proposed for the changes in constitution and function of the immune system that characterize immunosenescence. Such mechanisms interact with one another and other hallmarks of aging in complex ways. For example, aging leads to increased adiposity and decreased cellularity of bone marrow, which diminishes the production of the key cellular components of the immune system. Bone marrow stem cells also undergo senescence, leading to impaired proliferation and often a secretory profile that further reduces both production and function of immune cells. Those stem cells which persist are more likely to be of the myeloid lineage than the lymphoid lineage, further reducing the capacity of the marrow to support healthy immune function. This is exacerbated by concomitant involution of the thymus and changes in peripheral lymphoid tissues that also reduce the production of sufficient lymphocytes for normal immune function. Obesity and metabolic dysfunction, which commonly accompany aging, contribute further to inflammaging and bone marrow dysfunction [20]. Chronic infection and immune stimulation also exacerbate both the diminished protective ability of the immune system and inflammaging [10, 21].

Telomere shortening, changes in the microbiome, the extent of chronic antigenic stimulation, genetic background, epigenetic modulation of gene expression, and many other factors also play roles in the intricate causal pathways leading to the specific changes in immune function and subsequent health consequences for each individual. Although the precise factors that dictate aging outcomes for a particular animal cannot currently be fully understood, there are common patterns across individuals and species that broadly characterize immunosenescence.

5. Immunosenescence and the Innate Immune System

The main effector cells of the innate immune system include neutrophils, monocytes, macrophages, natural killer (NK) cells, and antigen‐presenting dendritic cells that connect the innate and adaptive systems. Although the innate immune system appears to be somewhat less severely altered by aging than the adaptive immune system, changes associated with immunosenescence occur in all of these cell types in humans and rodents. The data for dogs and cats are considerably sparser.

5.1. Neutrophils

In humans, neutrophil numbers remain constant or even increase with aging [5, 22, 23]. However, important aspects of neutrophil function are compromised, including chemotaxis, phagocytosis, and overall ability to destroy pathogenic organisms [5, 23, 24, 25]. Neutrophils also develop a more pro‐inflammatory cytokine production profile, potentially contributing to inflammaging [22, 24]. Interestingly, neutrophil function appears to be better preserved in centenarians compared with other geriatric individuals, suggesting a less severe immunosenescent phenotype might be associated with exceptional longevity [5].

The findings in dogs are less consistent. Several studies found no difference in neutrophil number or function between young and old [1, 26, 27, 28, 29]. However, one cross‐sectional study in Labradors found decreasing granulocyte numbers with age [30], and another study in Beagles identified a 39% decrease in neutrophil phagocytic function in dogs 10 years of age compared with dogs 1 year old [31]. The same study reported changes in messenger ribonucleic acid (mRNA) specific to factors associated with neutrophil migration and killing functions [31]. Finally, a cross‐sectional study involving both purebred and mixed‐breed dogs, owned and unowned, found an increase in neutrophil numbers with aging [32].

In cats, the evidence is even more limited. One study conducted in a research colony of domestic shorthaired cats found no difference in neutrophil counts between young and old cats [33], whereas another reported increases in granulocytes with age [34]. No published evaluations of changes in feline neutrophil function with aging were found.

5.2. Monocytes and Macrophages

Monocytes serve as precursors to dendritic antigen presenting cells and macrophages, but they also have distinct immune functions of their own. These include antigen presentation and both pro‐ and anti‐inflammatory cytokine production. These distinct functions are associated with different monocyte subtypes, conventionally designated classical, non‐classical, and intermediate monocytes [35]. As with neutrophils, most evidence suggests monocyte numbers in humans do not change much with aging, though some studies show increased numbers in populations with frailty.

However, there appear to be shifts in the proportion of various subtypes, as well as an overall decrease in functional capacity. Monocytes in elderly humans also have dysregulated cytokine production and sometimes produce lower amounts of pro‐inflammatory mediators such as interleukin 6 (IL‐6) and tumor necrosis factor‐ɑ (TNF‐ɑ) [5, 35]. Despite this, monocytes from older individuals also appear less effective at dampening ongoing inflammation in damaged tissue, suggesting that both pro‐ and anti‐inflammatory cytokine production can be decreased [35]. Through this and other mechanisms, monocytes are an important contributor to both diminished immune function and inflammaging [24, 35].

There are multiple subtypes of canine monocytes, though it is not yet clear how closely these correspond to those described in other species [36]. The data are conflicting in terms of changes in monocyte numbers with aging, with some studies finding no change [26, 37] and others finding increases [38] or decreases [32] in monocytes with age in dogs. The sparse evidence to date in cats has identified no changes in absolute monocyte number with age, though some studies show a relative decrease compared to other white blood cell types [33, 34].

In humans, macrophages show similar aging patterns to monocytes, including diminished chemotaxis, migration, and phagocytosis [5, 35]. Macrophages are also more likely to exhibit the pro‐inflammatory phenotype in older individuals [39]. These changes contribute to both the diminished effective functioning of the innate immune system and inflammaging.

In dogs, little is known about the effect of aging on macrophage number, type, and function. One study identified fewer intestinal macrophages in older dogs relative to other white blood cell types [40]. No data were found explicitly evaluating the effect of aging on macrophages in cats.

5.3. NK Cells

NK cells are cytotoxic non‐T lymphocytes that are particularly important elements in the defense against viral infection and neoplasia. Aging reduces the proportion of immature NK cells, which preferentially perform intercellular signaling functions, and increases the relative number of mature NK cells, with a predominantly cytotoxic phenotype [5, 24]. The number of NK cells stays stable or even increases with aging, but there appears to be decreased cytotoxicity and response to stimulation on a per cell basis, which might contribute to diminished overall innate immune function [23, 24, 25].

There has been much interest in characterizing canine NK cells because of their potential applications in cancer immunotherapy [41]. Despite this interest, it remains uncertain if the variable stages of maturation seen in humans and mice, with their distinct functional attributes, are also present in canine NK cells. Most research to date has identified no change in NK‐cell activity with aging [1, 41], though one study has identified some age and sex‐related differences in proliferative activity but not in cytotoxic capacity [27].

Much of the research characterizing NK‐cells in cats centers on how their function might be suppressed in some common viral and autoimmune conditions, such as infection with feline leukemia virus and feline immunodeficiency virus, and chronic gingivostomatitis [42, 43, 44]. However, only one study has specifically evaluated aging changes in this cell type, finding that both absolute and relative numbers of NK cells were decreased in senior cats compared with younger adults [33]. No evidence was found relating to aging‐related changes in NK‐cell subtype or function.

5.4. Dendritic Cells

Dendritic cells are important antigen‐presenting cells that mediate communication between the innate and adaptive immune systems through cytokine secretion and T‐cell activation [45]. In humans, there is no important change in the number or type of dendritic cells, but functionally they have impaired phagocytic capacity, decreased response to foreign antigens, and also decreased tolerance of self‐antigens. The patterns of cytokine secretion are also altered in the dendritic cells of older people, with a more pro‐inflammatory basal secretory pattern [5, 24, 46, 47].

Some changes in dendritic cell types and numbers have been reported with aging in dogs [1], but the functional consequences of these are not known. In cats, the basic properties of dendritic cells and their role in certain infectious and immune disorders have been studied [43], but little is known about how this cell type is altered by aging.

6. Immunosenescence and the Adaptive Immune System

The adaptive immune system, consisting of both cellular and humoral components, is generally more affected by aging than the innate immune system [5]. A major driver of the decline in immune function and the increased vulnerability to infectious and neoplastic disease in aging humans and dogs appears to be thymic involution [5, 16, 48, 49, 50] (thymic involution is believed to occur in cats as well, though specific studies documenting this are lacking [18, 51]). The thymus begins to regress early in life, and as it does so, individuals lose much of their ability to generate naïve T‐cells. This leads to a relative predominance of differentiated memory T‐cells, which preserve the ability to respond effectively to familiar antigens but impair the ability to respond to new infectious and neoplastic threats.

Caloric restriction, which is one of the most effective interventions for extending lifespan and health span in animal models, including dogs, has been shown to improve thymic function and mitigate immunosenescence in humans and mice [52, 53]. Obesity and metabolic dysfunction in mice fed a high‐fat diet (a common model of metabolic aging) [54, 55] have been shown to accelerate thymic atrophy and dysfunction [56]. These findings suggest a link between immunosenescence and other important features of aging, such as metabolic dysfunction and dysregulated nutrient sensing. Further elucidation of these relationships will facilitate understanding and targeting causal pathways involved in immune system aging.

In addition to thymic atrophy, cells of the adaptive immune system show mostly consistent patterns of change with aging, including diminished number or protective functionality, decreased response to antigenic stimulation, particularly novel foreign antigens, decreased proliferative capacity, and a shift toward pro‐inflammatory phenotypes [1, 5, 57, 58].

These changes in B cells and T cells are reflected in the humoral immune system, which also manifests altered functioning with aging. In humans, aged individuals have reduced numbers of naïve B‐ and T‐cells and a decline in the ability of B‐cells to class switch and produce antibodies targeting novel antigens [5, 24]. This impairs the response to both infectious organisms and vaccination.

Findings regarding changes in blood levels of various immunoglobulin classes are inconsistent, but in general humoral immune function appears impaired in the elderly even if certain immunoglobulin levels remain constant or even increase, likely due to the diminished ability to produce novel antibodies [59, 60, 61].

6.1. T Cells

Absolute lymphocyte counts decline with age in humans, and this has been linked to increased risk of disease and death [62, 63]. Naïve T‐cells decline in number, and differentiated memory T‐cells persist or increase [5, 64]. A relative increase in terminally differentiated memory T‐cells is associated with a diminished or oligoclonal receptor repertoire that reduces the ability to respond effectively to novel pathogens. This appears to be driven by chronic latent and periodically reactivated human cytomegalovirus (CMV) infection [10, 21]. Chronic stimulation of the immune system by CMV, with clonal expansion of CMV‐specific T‐cells, contributes to T‐cell exhaustion and decreased immune function.

A decreased CD4:CD8 ratio is also characteristic of immunosenescence in humans, with an inverted ratio (< 1.0) associated with increased disease and mortality risk [65, 66]. In the elderly, T cells are also prone to senescence and to a pro‐inflammatory phenotype as well as impaired functionality [5, 67]. Both decreased T‐cell function and a pro‐inflammatory secretory phenotype are characteristic of T cells altered by chronic CMV infection. By stimulation of the NF‐κB pathway and other mechanisms, CD28⁻ CMV‐specific T‐cells produce increased levels of pro‐inflammatory cytokines, such as IL‐1β, IL‐6, IL‐8, and TNF‐α, contributing to inflammaging [10, 21].

Similar changes have been identified in dogs, including overall decreased lymphocyte numbers [26, 27, 68, 69], decreased naïve and increased differentiated T‐cells [27, 28, 37, 70, 71, 72, 73], increased inflammatory phenotype [1, 74, 75, 76], decreased functionality [26, 27, 70, 77], and a decreased CD4:CD8 ratio in some, but not all, reports [1, 26, 29, 30, 37, 38, 78, 79, 80]. As seen in humans, there appears to be a diminished T‐cell receptor repertoire in aging dogs [81]. However, there is little evidence to suggest this is driven by chronic viral infection, as it is driven by CMV in humans. Chronic beta‐herpesvirus infections analogous to CMV have not been identified in dogs, and there are limited data on the prevalence or role of CD28⁻ T‐cells in immunosenescence in this species [73].

Available studies in cats show an aging‐associated decrease in total lymphocyte and T‐cell numbers and a decreased CD4:CD8 ratio [1, 33, 34]. It is unclear whether T cells also undergo senescence, a shift to a pro‐inflammatory phenotype, or decreased functionality in cats, though there is some indication of possible decreased lymphocyte proliferative capacity [82, 83]. There is scant information available concerning the relative proportion of naïve and differentiated T‐cells, repertoire diversity, or degree of clonality or T‐cell exhaustion with aging in cats. Although cats commonly have chronic latent alpha‐herpesvirus infections, such as feline herpesvirus 1, it is not known whether there is any beta‐herpesvirus analogous to CMV that might influence immune function with aging.

Some evidence suggests that in dogs caloric restriction mitigates the aging‐associated decline in total lymphocytes and T‐cells, CD8 and CD4 T‐cells, and possibly the shift from naïve to memory T‐cells in some cases [71]. This might be related to the attenuation of thymic atrophy by CR, as seen in humans and mice [52, 53].

6.2. B Cells and Humoral Immunity

B cells are the linchpin of the humoral immune system, responding to foreign antigens, stimulation by T cells, and other triggers to produce antibodies that protect against infection and modulate the overall immune response through cytokine secretion [84, 85]. Many of the changes seen with aging in human and mouse B‐cells are similar to those described in T cells.

B‐lymphocyte number typically declines with aging in humans and rodents, and there are changes in the proportion of B‐cell subtypes. For example, switched‐memory B‐cells, which most effectively recognize and respond to re‐exposure to familiar antigens, decline in number and function while late‐stage, pro‐inflammatory subtypes increase [5, 59]. Changes in B‐cell types and functions are driven by changes in bone marrow precursors and maturation, decreased T‐cell stimulation, and the increased production of mediators such as TNF‐ɑ which accompanies inflammaging [5, 59]. B cells in aged individuals are also less functional, showing reduced mitogen response, class‐switching capacity, and antibody production [59].

There is a decline in B‐cell numbers with age in cats [33, 34] and dogs [30, 38, 77, 86]. There is little direct evidence regarding aging and B‐cell function in these species. Some studies have also shown decreased mitogen response in dogs [87]. Data are mixed on the effect of aging on antibody production and response to challenges such as vaccination, and these measures of B‐cell function are often preserved in older dogs and cats [1]. Proliferative capacity of peripheral lymphocytes generally also appears impaired in dogs and cats, though there is little evidence regarding changes in specific cell types [70, 83].

7. Patterns of Pro‐ and Anti‐Inflammatory Mediators in Inflammaging

Inflammaging is a progressive, aging‐associated imbalance of pro‐inflammatory and anti‐inflammatory mechanisms that leads to unconstrained chronic inflammation and contributes to the development of age‐related disability, disease, and death [5, 14, 88]. It is one of the main hallmarks of aging [13], and it is driven by many factors, notably changes in the type and function of cells in both the innate and adaptive immune system, accumulation of senescent cells exhibiting SASP, accumulation of damage‐associated molecular patterns released from abnormal or dying cells, metabolic dysfunction, and changes in the microbiome [5, 88]. Although the causes of inflammaging are numerous and complex, ultimately it represents a dysregulation of the immune system that causes the normally protective processes of the system to become deleterious.

Immunosenescence involves an imbalance in the competing regulators of inflammation, including an increase in pro‐inflammatory signaling molecules such as IL‐1β, IL‐6, IL‐8, TNF‐α and C‐reactive protein (CRP) and decreases in anti‐inflammatory mediators such as IL‐10, IL‐1 receptor agonist (IL‐1Ra), transforming growth factor‐β (TGF‐β), adiponectin, and others [5, 88, 89, 90].

This imbalance affects the production, differentiation, and function of most immune system cells, leading to a vicious circle of progressive inflammation and deficient immune function. Eventually, this chronic inflammation alters the function of multiple organs and predisposes individuals to metabolic dysfunction and aging‐associated clinical disorders.

The limited evidence available for dogs identifies patterns of inflammatory mediators broadly similar to those seen in aging humans, suggesting inflammaging does occur in this species. However, there are differences, and it is not yet clear whether these represent true species differences in aging processes or merely gaps in the research data. Evidence in cats is scant.

Changes with age in IL‐1 levels have only been examined in a few reports. One found an increase in older female German shepherd dogs relative to young females, but no other associations with age [27]. A study of companion dogs of various breeds found no association between IL‐1β levels and age [91]. Another study evaluated IL‐1 production in monocytes from terriers and Labrador retrievers with lipopolysaccharide (LPS) stimulation and found no association with the age of the animals from which the cells were taken [87]. One study identified higher levels of IL‐1β converting enzyme in neutrophils of younger Beagles, suggesting they might have greater IL‐1β production than neutrophils of older dogs, though the effect of this on overall immune function and inflammaging is unclear [31].

This same study found no difference in IL‐6 production from stimulated monocytes. An earlier report indicated that young dogs had lower IL‐6 levels than adults but found no difference between adult, senior, and geriatric dogs [91]. Studies of Labrador retrievers [92], racing sled dogs [93], and dogs with systemic inflammatory response syndrome [94] have found no association between age and IL‐6 levels, though a more recent investigation of a diverse sample of purebred and mixed‐breed dogs did find a clear positive association between this cytokine and age [28].

This inconsistent pattern of findings is also seen in studies measuring TNF, which was positively associated with age in one study [28] but not in several other reports [27, 87, 91, 92, 94]. There is also limited evidence that IL‐8 levels increase in dogs with aging [28, 31], though this is not seen in every study [92, 93, 95]. One area of concordance is the lack of evidence that CRP levels are elevated with age in dogs or that this highly nonspecific and short‐lived biomarker can be used to evaluate inflammaging in this species [28, 94, 96, 97, 98].

Less is known about changes in anti‐inflammatory mediators with age, and much of the data come from narrowly focused in vitro studies. For example, it has been reported that the anti‐inflammatory cytokine IL‐4 and its receptor are more heavily expressed in older Beagles in some, but not all, regions of the spinal cord. However, the same study also found greater expression of the pro‐inflammatory cytokine IL‐2 and its receptor in older dogs [99].

No association between IL‐10 and age has been found in studies of Labrador retrievers [92] and sled dogs [93]. It has also been reported that expression of mRNA for IL‐10 in canine peripheral monocytes does not change with age [72]. Another study did find some evidence that IL‐10 production in whole blood stimulated with LPS was lower in blood from geriatric dogs than from young dogs, though such differences were not seen between middle‐aged and geriatric samples or with other stimuli [100].

An evaluation of mRNA abundance in adipose tissue from beagles of different ages found a pattern suggestive of “either an increased population of macrophages or increased inflammatory nature of adipocytes in adipose tissue of aged dogs,” but on the whole the evidence for a net pro‐inflammatory balance of immune system mechanisms in aging dogs is still quite sparse.

The evidence is even more limited for cats. Most studies of cytokine expression in cats focus on specific disease states rather than evaluation of changes with age in healthy individuals. Monocytes cultured from cats of different ages show elevated levels of pro‐inflammatory cytokines IL‐1β, IL‐6, and IL‐12 in older cats [101]. In the same study, TNF levels were not associated with age, and IL‐10 levels appeared to decrease in monocytes from older cats, though the difference did not reach statistical significance.

Cardiac myocytes from cats show variable cytokine production patterns between males and females, though some pro‐inflammatory cytokines are transcribed at lower rates in older cats (e.g., IL‐1, IL‐2, IL‐6, and TNF‐ɑ in females but of these only IL‐6 was significantly different in males), whereas TGF‐β transcription increased with age in both sexes [102]. Another study has reported higher levels of the acute‐phase protein serum amyloid A in geriatric cats compared with younger individuals [103]. IL‐8 levels have also been reported to be associated with age in cats [104].

As is common for many fundamental aspects of mammalian physiology, some of the general patterns of immunosenescence and inflammaging seen in humans and common laboratory animal species are present in dogs and cats as well. Often, pro‐inflammatory mediators increase with age, and anti‐inflammatory signals might decline. However, the evidence is still quite limited, and there are indications of some species differences. For example, baseline levels and trends over time in CRP have been identified in humans as a biomarker of aging and a potential predictor of aging‐associated disability and disease [105, 106, 107]. Most current evidence in dogs, however, does not find consistent or meaningful associations between this biomarker and age. This might be due to a true difference in species biology, but given that the associations in humans only emerge from analysis of large data sets, the difference might also be due to the paucity of veterinary data.

8. Clinical Consequences of Immunosenescence and Inflammaging

In humans, immunosenescence and inflammaging are key drivers of the increasing risk of disability, disease, and death in the elderly. The aging of the immune system is a major risk factor for infectious disease, autoimmunity, neoplasia, frailty, and many proximate causes of mortality [5, 108, 109, 110]. In veterinary medicine, these associations are less clearly elucidated.

There is certainly evidence that immune function declines and inflammation increases with age. However, fundamental epidemiologic data concerning the morbidity and mortality patterns for specific categories of disease at different ages is limited in veterinary medicine. This makes it more difficult to assess the possibility of associations between aging‐related changes in immune system function and clinical outcomes.

For example, there is extensive evidence showing that older dogs and cats are at increased risk of many of the same aging‐related diseases associated with immunosenescence in humans, including neoplasia and various degenerative diseases with an inflammatory component [11, 111, 112, 113, 114, 115]. A few systemic biomarkers of inflammation have been associated with some common diseases of aging in these species, such as mitral valve disease [116, 117], hypertrophic cardiomyopathy [102, 118], chronic kidney disease [119, 120, 121], and various forms of neoplasia [122, 123, 124], suggesting that inflammaging might be a risk factor for such aging‐associated conditions.

However, although elderly humans are clearly at increased risk from infectious disease due to immunosenescence and inflammaging [125, 126, 127, 128], this pattern is not evident in companion animals. Infectious disease risk is high in the very young, as it is in humans, but increases in infectious disease risk with age do not appear in epidemiologic studies of dogs or cats [11, 111, 114, 115, 129, 130]. Whether this is related to underlying differences in the influence of aging on immune function, differences in environmental risk factors for disease, a truncation of lifespan earlier in the life cycle for companion animals due to the prevalence of humane euthanasia, or simply gaps in the available data is uncertain.

Another aspect of immunosenescence in humans is the deterioration of vaccine response with age, which contributes to a greater risk of infectious disease [131, 132]. Vaccinal immunity and responsiveness might also decline with age in dogs and cats, though this is not always the case, and the influence on clinical susceptibility to disease is not clear [50, 79, 96, 133, 134].

Similarly, the risk of some autoimmune diseases, such as rheumatoid arthritis, increases with age in humans, and this is believed to be related to immunosenescence [128, 135, 136, 137]. In dogs and cats, however, the limited available data suggest that most autoimmune diseases occur in young or middle‐aged individuals, and the potential role of immunosenescence in triggering clinical autoimmunity is uncertain [138, 139, 140, 141, 142, 143, 144].

It is probable that there is a causal connection between immunosenescence and inflammaging, and many of the negative health outcomes of aging. However, more research is needed to confirm and characterize such a connection.

9. Potential Interventions to Mitigate Immune System Aging

A great variety of approaches have been proposed to mitigate immunosenescence and inflammaging and reduce the effects of these on clinical disease risk [128, 145, 146, 147, 148]. Some of the most commonly studied include:

• Lifestyle interventions

  • ○
    Diet and dietary supplements
  • ○
    Exercise

• Pharmacologic interventions

• Microbiome modulation

The majority of these interventions have only been evaluated in rodents and other laboratory models. However, there is some research suggesting caloric restriction and other dietary interventions, as well as supplements and drugs that target similar physiologic mechanisms, can mitigate some of the changes in the immune system associated with aging in humans [149, 150].

Caloric restriction has been shown to have a beneficial influence on some components of the immune system in dogs [71]. Other studies have evaluated the effects of nutritional variables [151], including changes in essential fatty acid ratios [87, 152, 153], and supplementation of short chain fructo‐oligosaccharides [154], yeast cell wall proteins [155], fiber [156, 157], and other nutraceuticals [153, 158, 159, 160] on various measures of immune function, from cytokines and immunoglobulins to T‐cell numbers and subtypes. Such studies have found some evidence of potentially beneficial effects, such as increased CD4:CD8 ratio [152, 154], improved neutrophil function following LPS stimulation [155], T‐cell and B‐cell proliferative responses [159] and pro‐inflammatory interleukin secretion [153]. However, many other indices of immunosenescence have been unaffected in these experiments, and it has not yet been demonstrated that such interventions can mitigate aging changes in immune function sufficiently to improve clinical outcomes.

There is little research investigating the effects of dietary manipulations and supplements on immunosenescence and inflammaging in cats [151]. Vitamin E supplementation might enhance lymphoproliferative response [161]. Both lymphocyte proliferation and function were improved by supplementation of salmon oil, arginine, and yeast‐derived nucleotides in cats in one report [162]. As in dogs, however, the clinical relevance of these effects for naturally aging cats has not yet been evaluated.

There is strong and growing evidence that long‐term physical exercise can mitigate the effects of aging on the immune system in humans. Physical activity increases naïve and regulatory T‐cells, reduces levels of pro‐inflammatory cytokines, delays the decline in thymic function, and retards or reverses other measures of immunosenescence and inflammaging [163, 164, 165]. Some of these effects are mediated by changes in skeletal muscle and adipose tissues and in energy metabolism [165], which are key components of the metabolic dysfunction that accompanies aging in humans as well as in dogs [20, 55].

Unfortunately, there are no studies specifically interrogating the effects of physical activity on aging‐related changes in immune system function. Some studies have evaluated short‐term changes in biomarkers of inflammation with acute exercise [98, 166, 167], but this is not a useful indicator of the long‐term adaptive responses to exercise that are believed to mitigate immunosenescence in rodents and humans. Fortunately, several longitudinal studies are under way that could eventually provide insight into the relationship between physical activity and aging‐related changes in immune function [76, 168, 169].

Numerous pharmacologic strategies for ameliorating changes in immune system function with aging have been proposed. Some of the best known of these, such as rapamycin and metformin, target dysregulated nutrient sensing and other hallmarks of aging and have been demonstrated to mimic some of the beneficial effects of caloric restriction [128, 147, 148]. Other strategies include drugs to block pro‐inflammatory cytokines or immune cell subtypes, senolytics to improve elimination of cells exhibiting SASP, and checkpoint inhibitors to modulate T‐cell function [128, 148].

The real‐world clinical benefits of these approaches remain to be determined.

Few of these strategies have been extensively evaluated in dogs and cats. Some studies have been done with rapamycin, metformin, and various purported senolytics in these species, though these have not explicitly evaluated effects on immunosenescence [170, 171, 172, 173, 174].

Modulation of the microbiome through probiotics, prebiotics, fecal microbiota transplantation, and other interventions has been proposed as a tool for mitigating immunosenescence and inflammaging [128, 147, 175]. A few veterinary studies have identified changes in a specific markers of immune function in response to probiotics intended to modify the microbiome [146, 154, 160, 176, 177, 178]. Although these preliminary findings are intriguing, there is not yet a robust body of evidence showing that it is possible to mitigate immunosenescence and inflammaging or improve clinical outcomes in aging dogs and cats by manipulation of the microbiome.

10. Conclusions

The cellular and molecular mechanisms of immunosenescence and inflammaging have been extensively investigated and well described in rodent models and in humans. There is less evidence available for dogs and cats, though what exists suggests both broad similarities and some potentially important species differences in these processes. Whether these are true differences in the fundamental biology of aging, reflections of different lifestyles and environmental exposures, or merely artifacts of insufficient data are not clear. Future research should focus not only on the details of immune system change with aging in dogs and cats but also on improving the foundational epidemiologic data needed to evaluate the clinical consequences of such change.

Given the trends in the existing evidence, and the highly conserved nature of aging mechanisms among mammalian species, it is likely that immunosenescence and inflammaging are important contributors to many of the manifestations of aging in dogs and cats, including chronic disease, frailty, declining quality of life, and ultimately mortality attributable to these aging‐associated conditions. Further elucidating the details of these processes, and investigating potential interventions to mitigate them, should be a major element of a preventive health approach that aims to extend lifespan and healthspan by targeting the underlying physiologic mechanisms of aging before they result in the clinical outcomes of disability, disease, and death.

Disclosure

Author declares no off‐label use of antimicrobials.

Ethics Statement

Author declares no institutional animal care and use committee or other approval was needed. Author declares human ethics approval was not needed.

Conflicts of Interest

Brennen A. McKenzie is a part‐time employee of Loyal, a private biotechnology company developing drugs for United States Food and Drug Administration (FDA) approval intended to extend healthy lifespan in dogs. Brennen A. McKenzie is a member of two scientific advisory boards associated with geroscience research: A Scientific Advisory Board (SAB) formed by Royal Canin to contribute to the scientific literature concerning healthy aging in dogs and cats; and a working group formed by Dr. Natasha Olby at North Carolina State University focused on establishing and promulgating consistent guidelines for diagnosis and assessment of canine cognitive dysfunction.