Geroscience and the aging cat

Introduction

Aging may be defined as “time-dependent functional decline” and is a relatively new field of research 1. Worldwide, average human life expectancy is increasing, although this is primarily due to a changing population demographic as a result of a reduction in mortality during childbirth, decreased early childhood mortality, and better control of infectious diseases. In many countries, average life expectancy is now 60 years or more, although in wealthier countries it is even longer – often over 80 years – as a result of both improvements in the treatment of previously fatal diseases and in the management of chronic conditions. However, increased lifespan does not always mean an increased health span. The challenge for medical professionals is to ensure that people not only live longer but also live free of chronic and debilitating diseases. These factors not only affect the quality of a person’s life, they have a large economic impact, both through the loss of productive members of society and from the financial cost of caring for unhealthy individuals.

The same situation is likely seen in our companion animals: better nutrition, vaccination and reproductive management, in addition to better diagnosis and treatment of disease, should increase the life expectancy of our pet cats and dogs, although comparison is difficult as there are no older longevity studies to contrast with more current ones 2 3. Recent UK studies put the average life expectancy of cats at 14 years 3 and dogs at 12 years 2 but cats can live up to 30 years ¹ or in a few cases (according to unverified reports) even longer. However, as with people, there is also an increase in chronic diseases associated with aging in pets, and as a result the veterinary profession should increasingly adopt approaches that consider the biology of aging itself to improve the health span of our companion animals in addition to the disease-focused approach currently practiced.

¹ AnAge database; see https://genomics.senescence.info/species

Physical signs of aging

The physical manifestations of aging can be observed in both humans and pets (Figure 1). In people these include alterations to the skin (which is highly dependent on lifestyle), changes to the musculoskeletal system (such as loss of muscle mass and loss of strength) and various conditions including osteoporosis (causing height reduction and spinal curvature) and osteoarthritis (OA) (causing loss of mobility).

In addition, there is a reduction in the “special” senses, most commonly vision and hearing, as well as cognitive decline. Age-related diseases in people include cardiovascular disease (including hypertension), neurodegeneration and cancer.

In cats, we also see physical changes associated with aging (Figure 2a) (Figure 2b), including alterations in the integumentary system which leads to differences in coat color and condition 4. Feline OA causes changes in mobility and grooming behaviors 5, and a reduction in special senses also occurs, along with cognitive decline 6. Age-related diseases in cats are considered to be chronic kidney disease (CKD), hyperthyroidism, cardiovascular disease (including hypertension), OA, diabetes and cancer 6. One UK study reported the top five causes of mortality in cats over 5 years of age to be renal disorders (13.6%), non-specific illness (12.6%), neoplasia (12.3%), mass-lesion disorders (11.6%) and neurological disorders (7.8%) 3. Mass-lesions disorders in this study were defined as disorders associated with a mass but with no specific etiology, so there is likely significant overlap with neoplasia, indicating that this and kidney disease are the most significant causes of mortality in older cats. The median age of cats that died due to non-specific illness was 16 years, and it can be hypothesized that this is due to a combination of co-morbidities and an increase in frailty associated with aging, which can both make it harder for veterinarians to determine the primary disease process and owners more reluctant to pursue diagnostics.

When does aging start?

The exact point at which aging starts to occur is poorly defined, and in people age-related changes will occur at different times in different body tissues. Research in cats is even less clear, but the current consensus is that the aging process begins at around 7 years of age 4 7. Data from indoor cats in the USA suggests that, by this age, the functional breeding period has ended, there has been a reduction in activity levels, and metabolic changes have occurred that result in increased body weight and an altered proportion of body fat 7. There is also a greater prevalence of many chronic diseases after 9 years of age 6.

It is important to note that aging will occur in all individuals, but that age-related disease will only affect some animals. There is now a movement to reserve the term “geriatric” for people where aging changes and age-related disease compromise an individual’s health and wellbeing, rather than referring to the provision of healthcare for the elderly population in general. This change in terminology should also be considered for our veterinary patients, given the increased numbers of healthy senior pets that are not affected by age-related disease (Figure 3).

The aging process

Underlying the physical manifestation of aging are complex biological and biochemical processes. The areas covered by the biology of aging are broad, with ongoing research investigating aging at a cellular level, at a systems level (using animal models of aging), and at a population level (using human cohort studies). The overall aim is to understand the aging process and to identify areas where intervention can be applied to improve longevity. It is recognized that if pathways can be manipulated to slow down the aging process, this will also slow down the development of age-related diseases, improving health span as well as lifespan.

In recent years there has been growing interest in canine models of aging, and the arguments for why they make a good natural template of human aging are to some extent also applicable to cats 8. However, unlike dogs, cats have only limited variation in lifespan due to breed, although there is considerable variation between feral cats and pet cats due to the risk of infectious disease and accidental death in the former group. Indeed, as noted above, cats have a longer maximum lifespan than dogs, 30 years compared with 24 years ¹, although average lifespan is reportedly similar, at 14 years in cats compared to 12 years in dogs 2 3.

¹ AnAge database; see https://genomics.senescence.info/species

The aging process causes frailty and increases the body’s susceptibility to disease, as well as decreasing resilience, which leads to a reduction in the ability to withstand concomitant stress. We commonly see this in aging cats where concurrent diseases have a far greater impact on a cat’s quality of life than they would in a younger cat. Studying the process of aging may enable the identification of critical time points where specific intervention or screening may have the greatest benefit for the individual.

The hallmarks of aging

Various "hallmarks" of aging have been identified (Box 1). To be an aging hallmark, a factor should fit the following criteria 1:

1. Manifest during normal aging.
2. Experimental aggravation should accelerate aging.
3. Experimental amelioration should retard aging and increase lifespan.

However, given that many factors are inter-related, it can be difficult for these criteria to be met, but for the purpose of this discussion we will consider them separately, and also review how they apply both to the aging cat and feline age-related disease.

Genomic instability

The first hallmark of aging is the accumulation of genetic damage, which occurs via exposure to exogenous and endogenous factors. Aging is associated with both an increase in cellular damage and a decrease in the repair processes, with damage affecting the nuclear DNA, the mitochondrial DNA, and the nuclear architecture 1. In cats the main implication of this is likely to be an increased risk of developing neoplasia with age 3, and as with many human cancers, tumor lines in the cat have been shown to have increased genetic instability.

Thyroid tumors are one of the commonest forms of feline neoplasia, leading to hyperthyroidism and affecting up to 8.7% of cats over 10 years of age; however, most veterinarians would not consider this condition to be “cancer” (Figure 4) (Figure 5). Feline hyperthyroidism is predominately due to a functional adenoma of the thyroid gland and resembles Plummer’s disease in humans. Less commonly it may be due to a thyroid gland carcinoma, although there are no reports of cats with thyroid autoantibodies, as seen with people suffering from Graves’ disease, the most common form of human hyperthyroidism.

The etiopathogenesis of feline hyperthyroidism is complex and multifactorial. Environmental compounds are believed to have an impact on the development of the disease 9, and whilst any dietary role is still to be clarified 10, changes in genetic expression have been identified and are thought to play a part; for example, overexpression of the c-RAS protein has been identified in hyperthyroid cats with adenomas 11, as have mutations in the G_sα Gene 12. Somatic mutations to the thyroid-stimulation hormone receptor gene have also been identified in affected cats 13.

Telomere attrition

This factor fulfills all the criteria for a hallmark of aging. Telomeres are protective structures which “cap” the ends of chromosomes and assist in maintaining genetic stability; however they shorten every time a chromosome replicates, and they are considered a separate hallmark of aging due to their importance (Figure 6) 1. Mammalian somatic cells contain only low (or no) levels of telomerase, a ribonucleoprotein which can repair telomeres; this means that telomeres have a naturally poor ability to repair, which can lead to persistent DNA damage. As the telomeres shorten with age, they eventually reach a critical level which results in them being detected by the body as damaged DNA, triggering cell senescence and/or apoptosis. Feline-specific research has shown that telomere shortening occurs in CKD and with age in blood cells; there is also increased expression of telomerase in some tumors, which may allow neoplastic cells to proliferate unchecked.

Epigenetic alterations

Epigenetic alteration is defined as a heritable change that does not affect the chromosomal sequence but results in an alteration in gene expression. Three different types are recognized:

• DNA methylation: this is a biological process whereby methyl groups are added to a molecule of DNA, altering the activity of a DNA segment without changing the genetic sequence. The process is essential for normal development and is linked to a number of key physiological and pathological processes; however, aging is associated with a decrease in global DNA methylation and an increase in local methylation 1. Recent work has focused on using this as an epigenetic “clock” in people, with studies showing similar changes in canids and other mammals 14.
• Histone modification: Histones, and in particular sirtuins, are a group of mammalian proteins that play a role in cellular health. Sirtuins are encoded by SIRT genes; proteins produced by SIRT1, 3 and 6 are known to contribute to healthy aging 1, and Sirtuin 1 has been shown to suppress inflammation in feline fibroblasts 15. There has also been some preliminary investigation into how resveratrol (a sirtuin activator) is metabolized in cats, as it may eventually be useful as a dietary additive to reduce pro-inflammatory states associated with aging 16.
• Chromatin remodeling: a decrease in chromosomal proteins occurs in both aged and pathologically aged cells, as well as changes to the chromosomal architecture. Under- and over-expression of heterochromatin protein-1-alpha is known to have an impact on longevity and muscular strength in flies, and heterochromatin has a role in telomere assembly, indicating that epigenetic factors have an impact on telomere length.

In future the ability to enable and control epigenetic alteration may offer scope for genetic manipulation, which in turn could result in better longevity, as well as – and more importantly – aiding retention of function and reduction of frailty, thus improving health span as well as lifespan.

Loss of proteostasis

Proteostasis is the ability to stabilize correctly folded protein and involves mechanisms that refold unfolded proteins or remove then via degradation or autophagy. Aging is associated with altered proteostasis, and in people chronic expression of unfolded, misfolded or aggregated proteins is linked to some age-related disease 1. Amyloid β plaques have been found in older cats with behavioral dysfunction, and tau phosphorylation is associated with seizures in aging cats. Feline mortality due to behavioral and neurological disorders is estimated to be 1.3% (median age 16 yrs.) and 7% (median age 15.1 yrs.), respectively 2, although neoplasia may be a contributory cause in some of these cases. Pancreatic amyloid is associated with feline diabetes, whilst amyloidosis is a not-uncommon finding on postmortem examination in cats with CKD. Manipulation of autophagy has been shown to promote longevity experimentally, and there is ongoing research into the use of rapamycin in canine aging, a molecule shown to possess immunosuppressive and anti-proliferative properties in mammalian cells 17.

Deregulated nutrient sensing

Nutrient sensing is a cell's ability to recognize and respond to fuel substrates (such as glucose) and it is thought that alterations in nutrient sensing may be linked to aging. For example, insulin, and the insulin-like growth factor 1 (IGF-1) pathway, have been well conserved throughout evolution, and manipulations to this pathway (and also certain targets for the pathway) have been linked to longevity. More broadly, caloric restriction is known to increase lifespan for many species, both through activation of this pathway and other associated key protein groups that form the nutrient sensing systems. Current research in dogs is looking at the potential of drugs such as rapamycin, which mimics the effects of dietary restriction by suppressing a nutrient-sensing pathway, although the effect of controlled calorie intake on these pathways has not yet been studied in the cat. However, declining serum IGF-1 levels have been reported in senior cats 18, and declining growth hormone (GH) and IGF-1 are described in normal ageing in other species. This may be a defense mechanism, whereby decreases in GH and IGF-1 lead to reduced cell growth, metabolism and lower rates of cell damage in an attempt by the organism to extend its lifespan. Decreased GH and IGF-1 have also been reported in premature ageing in laboratory situations, so in some cases these defensive measures may eventually aggravate ageing. Declining IGF-1 levels in older cats has been investigated to determine if this impacts lymphocyte homoeostasis, as declining T-cell counts are associated with immunosenescence, but as yet no direct effect on peripheral blood lymphocytes has been found 18. A pathological increase in serum IGF-1 secondary to increased GH secretion has been described in cats with acromegaly caused by a pituitary tumor. If left untreated this leads to increased cell growth and metabolism which affects the lifespan, as affected cats have insulin resistant diabetes mellitus and usually die from congestive heart failure, CKD or signs linked to an expanding pituitary mass.

Obesity is now a well-recognized problem in our pets and has multiple metabolic effects (Figure 7); it seems likely that obesity will impact on a cat’s lifespan, in part through deregulation of these nutrient sensing pathways, although this is yet to be explored. Shorter lifespan time has been associated in cats with both low and very high (i.e., 9) body condition scores (BCS) 19.

Mitochondrial dysfunction

Mitochondrial dysfunction has been shown to accelerate aging in mammals. Reactive Oxygen Species, or ROS (chemically reactive substances containing oxygen) were previously thought to cause mitochondrial dysfunction through free radicals, but they are now considered to be signals that help maintain homeostatic responses within the cell, although once they pass a threshold they may aggravate age-associated damage 1. A study from 2013 20 indicated that male cats might be at greater oxidative risk than females, although the significance of these results on aging is unclear given the change in thinking on the role of ROS since this paper was published. In people, endurance training and intermittent fasting promote longevity by decreasing mitochondrial degeneration, whilst telomeres and sirtuins are also thought to have a protective role 1.

Cellular senescence

Cellular senescence is the stable arrest of the cell cycle coupled to stereotypical phenotypic changes; it can be triggered by telomere shortening and other age-associated stimuli 1. Senescence does not occur in all aged tissues; accumulation of senescent cells within tissues can be due to an increased rate of production of such cells or (possibly due to a compromised immune response) a decrease in clearance 1. It is thought that senescence is a natural process designed to remove damaged and potentially oncogenic cells – which will be beneficial – but if there is a reduction in both clearance and replacement of these senescent cells as tissue ages, this could contribute to the aging process 1. Senescent cells also have a pro-inflammatory secretome (the set of proteins expressed by an organism and secreted into the extracellular space) which might contribute to aging. In addition to shortened telomeres in the renal tissue of cats with CKD, one study noted an increased concentration of senescence-associated β-galactosidase-stained cells, although this did not reach statistical significance 21. Furthermore, there is evidence that cellular senescence could be associated with the chronic inflammatory response and fibrosis that drives feline renal disease. The senescence may cause a decrease in the proliferative potential of renal tubular epithelial cells, contributing – along with the effects of shortened telomere length –towards the development of CKD 22.

Stem cell exhaustion

Stem cell exhaustion reduces the overall regenerative processes of tissues, not just through a lack of replacement of healthy cells, but also due to a reduction in “immuno-senescence”, the body’s immunological processes for removing senescent or damaged tissues 1. This is thought to result from a reduction in hematopoiesis, leading to anemia, an increased risk of myeloid malignancies, and a reduction in adaptive immune cells 1. Studies have demonstrated a reduction in T-cells, B-cells and natural killer cells in senior (10-14 years) compared with younger (2-5 years) cats 23. Although these changes in immunity do not seem to have an effect on susceptibility to infection if a strong immune response develops as a young adult, they do have an impact on the development of an antibody titer to a novel vaccine. Whilst a summary of research into feline immune-aging was published in 2010, no feline-specific studies have been reported in this field since then 24.

Altered intercellular communication

Aging also affects the way cells communicate with each other, be it endocrine, neuroendocrine or neuronal in nature. Overall, aging leads to dysregulation of neuro-hormonal signaling, increased inflammatory reactions, changes in the pericellular and extracellular environment, and a decrease in immune-surveillance, thus increasing the risk from pathogens and malignant cell transformations 1. Changes in intracellular communication are also likely to play a role in the progression of renal fibrosis in feline CKD 22. The pro-inflammatory state in aging is often referred to as “inflammaging”, and is a combination of many of the factors already discussed 1.

What can we do now for our cats?

Research into these different factors may lead to new ways to tackle aging before disease appears, but based on what we currently know, the most important message for veterinarians is actually very basic – namely, that maintaining an optimal body condition for cats is likely to have a positive effect on both lifespan and health span. Studies show that cats with maximum BCS of 6/9 and greater are at an increased risk of various diseases 25, although only a score of 9/9 was associated with a shortened lifespan 19. As a result, to optimize health and longevity, maintaining a BCS of between 5 and 6 is likely to give the best outcome for our pet cats.

Looking to the future, we can hypothesize that diets, nutraceuticals or therapeutics will be developed that can be initiated in adulthood (or at the earliest detection of age-related changes) to help maintain health. Mechanisms that encourage DNA repair, lengthen telomeres (or prevent their shortening), increase autophagy, improve senescent cell removal, and augment stem cell production (which will assist the production of populations of healthy cells) will all have a cascade effect to enhance the health span and likely lifespan of our pets. Although the “fountain of youth” is only a mythical concept, there are realistic expectations that some interventions will be developed that target many of these mechanisms, and – for cats in particular – renal health and function could be an important focus, given the prevalence of CKD. However, since all of these processes are interrelated, a substance that has a positive effect on one tissue may have a negative effect on other factors, so much more research is still required.