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Common physical and functional changes associated with aging in dogs

Article  in  Journal of the American Veterinary Medical Association · January 2015

DOI: 10.2460/javma.246.1.67 · Source: PubMed

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Reference Point
Common physical and functional changes
associated with aging in dogs
Jan Bellows, DVM; Carmen M. H. Colitz, DVM, PhD; Leighann Daristotle, DVM, PhD;
Donald K. Ingram, PhD; Allan Lepine, PhD; Stanley L. Marks, BVSc, PhD;
Sherry Lynn Sanderson, DVM, PhD; Julia Tomlinson, BVSc, PhD; Jin Zhang, PhD
I n the broadest sense, aging refers to the natural, pro-
gressive series of life stages beginning with concep-
tion and continuing through development, maturation,
and senescence. Most often, however, the term is more
narrowly used to refer to the complex set of biological
changes occurring in older individuals that result in a
progressive reduction of the ability to maintain homeo-
stasis when exposed to internal physiologic and exter-
nal environmental stresses.1 These changes ultimately
lead to decreased vitality, increased vulnerability to dis-
ease, and eventually death.
Older dogs make up a substantial proportion of
the pet dog population in the United States. One sur-
vey,2 for example, estimated that 30% to 40% of the 78
million pet dogs in the United States in 2007 were ≥
7 years old, and a more recent survey3 suggested that
the percentage of older dogs may be as high as 49%. Of
course, the rate at which individual dogs exhibit overt
signs of aging is affected by a number of factors, includ-
ing breed, adult body size, genetic makeup, exposure
to injuries and disease, and nutritional status. When all
breeds are considered together, the mean lifespan of do-
mestic dogs is approximately 13 years.4 However, body
size substantially affects lifespan in dogs.5–7 Thus, be-
cause of their shorter lifespans, giant- and large-breed
dogs (ie, dogs with a mature body weight ≥ 22.7 kg
[50 lb]) should probably be classified as senior when
they are 6 to 8 years of age and as geriatric when they
are ≥ 9 years of age. Medium- and small-breed dogs (ie,
dogs with a mature body weight < 22.7 kg) may be clas-
sified as senior when they are 7 to 10 years of age and as
geriatric when they are ≥ 11 years of age. Regardless of
From All Pets Dental, 17100 Royal Palm Blvd, Weston, FL 33326
(Bellows); Animal HealthQuest Solutions LLC and All Animal
Eye Care Inc, 300 Central Blvd, Jupiter, FL 33458 (Colitz);
P&G Pet Care, 8700 Mason-Montgomery Rd, Mason, OH
45040 (Daristotle, Lepine, Zhang); Nutritional Neuroscience
and Aging Laboratory, Pennington Biomedical Research Cen-
ter, Louisiana State University, Baton Rouge, LA 70808 (In-
gram); the Department of Medicine and Epidemiology, School
of Veterinary Medicine, University of California-Davis, Davis,
CA 95616 (Marks); the Department of Physiology and Pharma-
cology, College of Veterinary Medicine, University of Georgia,
Athens, GA 30602 (Sanderson); and Twin Cities Animal Reha-
bilitation Clinic, 12010 Riverwood Dr, Burnsville, MN 55337
(Tomlinson). Dr. Daristotle’s present address is 4272 State Rte
732 W, Eaton, OH 45320.
Address correspondence to Dr. Lepine (allan.lepine@effem.com).
JAVMA, Vol 246, No. 1, January 1, 2015
GAG
ABBREVIATIONS
Glycosaminoglycan
GI Gastrointestinal
HPA Hypothalamic-pituitary-adrenal
T4 Thyroxine
TSH Thyroid-stimulating hormone (thyrotropin)
the specific age cutoffs used, senior and geriatric dogs
can all be considered to be aged and to likely have at
least some changes associated with aging.
Some changes associated with aging can be consid-
ered favorable. For example, aged dogs often are well-
behaved and have well-established habits. Other aging
changes are neither positive nor negative, such as gray-
ing of the muzzle or a moderate reduction in activity
level. Less desirable changes are those associated with
illness, changes in mobility, or the development of be-
havioral problems. Collectively, deteriorative changes
that negatively affect an aged dog’s overall quality of life
are referred to as senescence.8
Several theories have been proposed to explain the
phenomena of aging and senescence.9 Many of these
focus on genetic controls, such as the somatic muta-
tion and gene regulation theories. Others examine the
impact of temporal changes on homeostatic mecha-
nisms of various body systems or the accumulation
of damaging products as a result of cellular aging. For
example, the oxidative stress theory postulates that ag-
ing is linked to energy expenditure and the cumulative
cellular damage caused by free radicals derived from
external sources as well as internal sources such as mi-
tochondrial respiration and immune cell reactions.10,11
However, none of these theories by itself explains all of
the changes that are observed during aging, and many
of the theories that have been advanced are not neces-
sarily mutually exclusive. A more cogent view is that
aging and senescence are multifaceted processes influ-
enced by genetics and a myriad of internal and external
environmental factors.
Naturally, many older dogs are cherished fam-
ily members whose owners are committed to provid-
ing them with the best of care. When examining older
dogs and when providing owners of older dogs advice
regarding their care, veterinarians should have an ap-
preciation of the types of changes that reflect typical
age-related changes (ie, healthy aging) versus an under-
Vet Med Today: Reference Point 67
lying disease or abnormality. To that end, the present
report reviews some of the most common health-relat-
ed changes observed in older dogs as they age.
General Physical Changes
Associated with Aging
Typical physical changes associated with aging in
older, healthy dogs manifest as changes in behavior, ap-
pearance, and daily function, and it is these changes that
are most often noticed by pet owners. Typical behavioral
changes include changes in sleep cycle, responses to ver-
bal commands, and interactions with family and other
pets, which could reflect functional changes in cognitive
and behavioral health. Appearance changes include a
gray, dull, dry coat; loss of muscle mass; and develop-
ment of cataracts and nuclear sclerosis, which could re-
flect functional changes in skin and coat, weight, body
condition, and vision health. Functional changes include
decreased activity and mobility and decreases in vision,
smell, and hearing, which could reflect functional chang-
es in musculoskeletal system and special senses health.
These changes can happen in the absence of any disease
process as part of normal aging.
Cognitive and Behavioral Changes
Age-related changes in the cognitive and behavior-
al domains can be expected in most dogs with advanc-
ing age. Some of the changes that occur in aged dogs
without underlying systemic disease include changes
in cognition, affect, sleep patterns, general activity, and
motor performance; many of these changes likely result
from underlying neurodegenerative processes.12–14
Formal, laboratory-based methods for assessing
age-related changes in cognitive behavior in dogs have
expanded greatly over the past 2 decades. Using meth-
ods adapted from cognitive assessment techniques in
nonhuman primates, Studzinski et al15 and Tapp and
Siwak16 developed the Toronto General Test Apparatus
to identify cognitive impairment in dogs and evaluat-
ed age-related changes in cognitive abilities in Beagles
across several cognitive domains. Age-related declines
were reported in spatial memory, executive function,
and concept learning. What emerged from these studies
was the observation that older dogs could be separated
into impaired and unimpaired animals. The perfor-
mance of unimpaired dogs generally resembled that of
their younger counterparts, whereas impaired dogs had
notable impairments in 1 or more domains of behav-
ioral performance. Impairments were also predictive of
altered sleep-wake cycles, an increased likelihood of be-
havioral stereotypies, and decreased social contact with
humans, which are consistent with behavioral changes
reported in aged pet dogs.14 By contrast, unimpaired
aged dogs had behavioral patterns that differed from
those of both young and age-impaired dogs. Compared
with young dogs, unimpaired aged dogs showed lower
levels of activity as well as a shift from spending a lot of
time interacting with humans to simply spending more
time near humans.14
Analyses of biochemical and anatomic aspects
of aging in dogs have revealed underlying neurologic
changes related to cognitive and behavioral perfor-
68 Vet Med Today: Reference Point
mance.14,15,17–21 Further investigation of these changes
found a correlation between cognitive disorders in aged
dogs and the accumulation of oxidative damage in brain
cells.18,22 The brain appears to be particularly suscep-
tible to the damaging effects of oxygen-free radicals.23
Overall, these findings suggest that biological processes
of brain aging that affect the behavior of older dogs can
start as young as 7 to 8 years of age.14
Skin and Coat Changes
With advancing age, several changes occur in the
skin and hair coat of dogs. Cellular atrophy increases in
both the epidermis and dermis. Follicles may also atro-
phy, resulting in areas of hair loss.24 The skin loses elas-
ticity and becomes less pliable as a result of increased
calcium content and pseudoelastin in the elastic fibers.
This loss of elasticity is often accompanied by hyper-
keratosis of both the skin and hair follicles. Loss of me-
lanocytes in the hair follicles and reduced activity of
the enzyme tyrosinase result in the production of white
hairs, which are often observed around the muzzle and
face of older dogs.25 Changes in sebum production in
older animals can result in scaly skin and cause the hair
coat to become dry and dull. Highly sulfated GAGs are
present in the basement membranes of hair follicles,
and their concentration increases with age. A recent ret-
rospective study26 documented that older dogs are more
likely to have a diagnosis of cutaneous neoplasia, with
10 to 15 years being the most frequent age range and
lipomas, adenomas, and mast cell tumors representing
the most common types.
Changes in Body Weight and Condition
As animals age, their basal metabolic rate naturally
slows. This decline is caused primarily by proportional
changes in body composition that include decreased
lean tissue and water contents and increased fat con-
tent. For example, a study27 comparing young and old
dogs reported that the body fat percentage of young
adults was between 15% and 20%, while that of older
dogs was between 25% and 30%. Most, but not all, dogs
voluntarily reduce physical activity as they enter their
senior years. It is estimated that a dog’s total daily en-
ergy requirements may decrease by as much as 30% to
40% during the last third of its life as a result of reduced
activity and decreased metabolic rate.28 For these rea-
sons, some aging dogs are at increased risk for becom-
ing overweight. However, a greater proportion of dogs
> 12 years of age are underweight, compared with pro-
portions for other age groups.29 This may be related to
age-related sarcopenia in older dogs.
Some dogs do remain active and athletic well into
their senior years. Because physical activity helps off-
set age-associated losses of lean body tissue, the basal
metabolic rate in older dogs that remain active may not
decrease substantially.
Musculoskeletal Changes
Lean body (muscle) mass and bone mass decrease
as dogs age. Both the number and size of myocytes de-
crease with age.
JAVMA, Vol 246, No. 1, January 1, 2015
 Sarcopenia is a syndrome seen during aging in the
absence of disease.30,31 The current definition of sarco-
penia in people proposed by the European Working
Group on Sarcopenia in Older People is “a syndrome
characterized by progressive and generalized loss of
skeletal muscle mass and strength with a risk of ad-
verse clinical outcomes, such as physical disability,
poor quality of life, and death.”30 In people, sarcopenia
is associated with increased mortality rate and adverse
effects on muscle strength, immune function, and qual-
ity of life.30,31 Although little information on the effects
of sarcopenia in aging dogs is available at this time, it is
a recognized syndrome in aging dogs, and there is every
reason to believe that its effects on dogs are similar to
those reported in people. A recent unpublished studya
of Labrador Retrievers found that healthy geriatric dogs
(> 8 years of age) had significantly lower mean epaxial
muscle area than did healthy young dogs (1 to 5 years
of age).
Protein requirements sufficient to support protein
turnover may actually increase in older dogs.32 A study29
comparing protein requirements in young versus older
Beagles showed that older dogs required approximately
50% more protein than did young dogs to maintain ni-
trogen balance and maximize protein reserve. In addi-
tion, protein turnover was reduced in older dogs, even
at the highest level of protein fed. Failure to recognize
these nutritional needs as dogs age can accelerate the
weight loss and sarcopenia that occur in geriatric dogs.
The cortices of the long bones become thinner, less
dense, and brittle as dogs age.33,34 The composition of
the articular cartilage matrix also changes with age.
Specifically, a reduced number of chondrocytes leads
to decreased production of GAGs, type 1 collagen, and
chondroitin sulfate.33,34 As a result, aging cartilage grad-
ually becomes less resilient and has limited ability to
regenerate in response to intense activity or trauma.
Changes in the Special Senses
Advancing age may lead to a general decline in a
dog’s ability to react to stimuli and to changes in the
special senses, including vision, hearing, and olfaction.
The most common age-related change in the eyes
of dogs (especially those that are > 6 years of age) is
development of nuclear (lenticular) sclerosis, which
appears as bilateral bluish-gray haziness in the nucleus
of the lens.35,36 It is caused by compression of existing
lens fibers as a result of new fiber formation, leading to
increased density of the lens and an increase in the re-
fractive index of the lens nucleus. Although many dog
owners confuse the resulting bluish haze with cataracts,
nuclear sclerosis does not usually affect a dog’s vision,
except in severe cases. Night vision loss is gradual and
very common in aging dogs; however, most owners and
veterinarians blame the lens changes. Some dogs with a
gradual onset of vision impairment do not demonstrate
signs of these changes until their hearing is diminished,
which illustrates the importance of hearing over vision
in dogs.
Hearing impairment caused by cochlear degenera-
tion is common in older dogs.37 Changes seen morpho-
logically are quantitatively and qualitatively similar to
JAVMA, Vol 246, No. 1, January 1, 2015
those that occur in aging humans.37 Although there are
generally no direct health risks associated with hearing
loss, owners are often acutely aware of these changes
and may be concerned for their dog’s safety and quality
of life. In some dogs, age-related changes in cognitive
function may manifest as apparent hearing loss.
Clinical changes in the sense of smell have not
been documented in dogs as a manifestation of ag-
ing, although pathological changes have been demon-
strated. Because dogs and humans age similarly, it has
been hypothesized that cognitive impairment and ol-
factory function may be linked in dogs, as they are in
humans.38,39 In fact, impaired olfactory function is asso-
ciated with the risk of developing cognitive impairment
in humans.40 On the basis of published data, it would be
logical to assume that olfactory function in dogs would
be diminished with advancing age. In a study41 of dogs
> 14 years of age, olfactory epithelium was atrophied,
as was the olfactory nerve layer. In addition, there were
age-related vascular amyloidosis, astrocytic gliosis, and
ubiquitin deposits within the olfactory bulb.41 An inter-
esting difference between human and murine olfactory
bulbs and canine olfactory bulbs is that dogs do not
have β-amyloid deposition in this location, despite hav-
ing it elsewhere in the cerebral cortex.41–44 β-Amyloid has
been found in the olfactory epithelium of aging dogs.45
To clinically evaluate changes in olfaction in aging dogs,
researchers in 1 study39 developed a novel paradigm to
evaluate odor discrimination in dogs and identified a
weak, though not significant, decline in odor discrimina-
tion with age. However, the paradigm needs to be evalu-
ated with a larger group of dogs as well as with untrained
dogs to rule out artifacts before any conclusions can be
made. Nevertheless, given clinical information for other
species, the histologic data, and the preliminary clinical
data for dogs, it is likely that a dog’s sense of smell di-
minishes with age.
Oral and Gingival Changes
In dogs that do not have evidence of plaque, calcu-
lus (tartar), gingivitis, or periodontal disease, there are
no changes to the visual appearance of the gingiva and
dental hard structures as dogs age. Plaque normally at-
taches daily on the crowns of teeth unless mechanically
or chemically removed. Calcium and phosphorus in the
saliva then mineralize the plaque to produce calculus.
It is common to find plaque and calculus on the teeth
of healthy aged dogs.
Mouth size is a significant risk factor for periodon-
tal disease in dogs. Clinically, larger aged dogs may
have healthy mouths and teeth with little plaque and
calculus accumulation, while smaller dogs may have
greater accumulations of plaque and calculus, are more
likely to develop periodontal disease at an early age,
and tend to show more severe disease, compared with
larger dogs.46 Reduced jaw size and crowding of teeth
may be predisposing factors for dental disease in small-
er dogs. In addition, toy-breed dogs are more likely to
have malocclusion problems, which may facilitate the
deposition of subgingival plaque that is more difficult
to remove through either chewing or home care. As
periodontal disease progresses, there is destruction and
Vet Med Today: Reference Point 69
loss of alveolar bone along the roots of teeth. Because
smaller dogs have a lower ratio of mandibular size to
tooth volume, compared with the ratio in larger dogs,
the loss of bone has a greater impact.47
Owner intervention in preventing plaque accu-
mulation can have a major impact on the establish-
ment and progression of periodontal disease in dogs.
If the owner strictly controls plaque, the periodontium
remains healthy and the teeth should remain well-
anchored in their alveoli. Conversely, if the owner does
not establish a plaque control regimen, periodontal dis-
ease will usually occur, leading to gingival inflamma-
tion and, eventually, tooth loss.
Gastrointestinal Tract Changes
With advancing age in dogs, several structural and
functional changes take place in the GI tract. These in-
clude reduced salivary and gastric acid secretion; de-
creased villus size, rate of cellular turnover, and colonic
motility; and alterations in the intestinal microbiota.28
One study48 found that age and dietary fructooligosac-
charide supplementation affect the intestinal microbiota
in dogs. Another study49 found that the microbiota in
the large bowel changes as dogs age. In a third study,50
the authors found a difference in metabolic activity in
the feces of 4-year-old dogs, compared with that in feces
of 10-year-old dogs. Age-related changes in fermentation
products in that study50 suggested an alteration in bacte-
rial metabolic activity or in the rate of intestinal absorp-
tion of these compounds. Although it has been theorized
that aging of the GI tract leads to a decreased ability to
digest and absorb nutrients, studies51–53 of healthy older
dogs indicate that most dogs appear to maintain diges-
tive efficiency as they age. This makes calculating en-
ergy provisions for aged dogs relatively straightforward.
Because maintenance energy requirement decreases by
approximately 20% and energy digestibility remains
constant, aged dogs should be offered a reduction in
energy equivalent to an approximately 20% decrement,
although individual variations in metabolic rates exist.54
Using radiopaque markers and radioisotopic meth-
ods, researchers55 have demonstrated slowing of gastric
emptying after consumption of large solid meals and a
delay after consumption of large liquid meals in older
people. Results of a study56 involving rats support the
concept that changes in the aging GI tract result in in-
creased satiety. The effects of age on the gut microbi-
ota have been well studied in people. A recent study57
showed that although microbial composition and gut
ecosystems are similar in young adults and seniors, they
differ significantly from those of centenarians. Changes
in the microbiota of centenarians are associated with
inflammaging (a chronic, systemic inflammatory state)
and a reduction in symbiotic bacterial species that have
anti-inflammatory properties.
The liver is the central organ in the regulation of
nutrient metabolism, xenobiotic metabolism, and de-
toxification. Evidence from humans and rodents has
indicated that aging leads to marked changes in liver
structure and function.58 The aged liver is characterized
by decreases in weight, blood flow, regeneration rate,
and detoxification rate, which are related to an increased
risk of liver abnormalities in the elderly.58 Aged dogs are
70 Vet Med Today: Reference Point
affected by many of the same chronic hepatic disorders
seen in elderly humans, with age-related alterations in
liver function influenced by diet. Molecular microarray
analysis of liver tissue from aged and young-adult dogs
revealed that genes related to inflammation, oxidative
stress, and glycolysis were upregulated, whereas genes
related to regeneration, xenobiotic metabolism, and
cholesterol trafficking tended to be downregulated in
aged liver tissue.59
In humans, age-related changes in exocrine pancre-
atic secretion include decreased flow rates and dimin-
ished production of bicarbonate and enzymes; howev-
er, functional and structural changes do not occur in
everyone, nor do they progress continuously.60 These
changes are generally not associated with clinical mani-
festations and do not require substitution treatment
because the reduction in enzyme secretion is typically
well below the 80% to 90% decrease in exocrine func-
tion at which maldigestion occurs.60–62 There is also a
decrease in secretin-stimulated secretions.60–62
Cardiac Changes
Normal vascular changes that occur with age in
dogs include hyaline thickening of blood vessels and
increased calcium deposition in the intima of the aorta
and sections of the peripheral arteries.63 Together, these
changes contribute to an increased load on the heart,
which can eventually lead to the development of con-
gestive heart failure.
Beginning in midlife, cardiac output gradually de-
creases and can decrease by as much as 30% in geriatric
dogs.63 Maximum heart rate and oxygen consumption
during exercise also decrease as animals age. For exam-
ple, a study64 that compared cardiovascular responses
during exercise between young and old dogs reported
that aging was associated with a loss of cardiovascular
reserve and adaptability. These changes are presumed
to contribute to cardiovascular disease in older dogs.
The effects of aging on contractile performance,
stiffness, and contraction time of the left ventricle
were evaluated in 8 young (mean ± SEM age, 27.5 ±
2.5 months) and 7 old (128 ± 20.5 months) Beagles.65
A major finding of this study showed that increasing
age was associated with an increase in the stiffness of
the left ventricle, both in systole and diastole, as well
as a prolonged duration of contraction. A more recent
study66 evaluated the effects of age on transmitral and
pulmonary venous flow in client-owned dogs compris-
ing 27 breeds that ranged from very young (3 months
of age) to very old (19 years of age). Results indicated
that a gradual decrease in the rate of left ventricular
relaxation, an increase in myocardial stiffness, and an
enhanced late diastolic filling occur with aging in dogs.
Although there are limited studies in dogs evaluating
the effects of aging on cardiac function, there do appear
to be some age-related changes that could adversely af-
fect the ability of older dogs to respond to cardiac stress
in the same way as younger dogs.
Respiratory Tract Changes
Aging changes in the respiratory system have been
well characterized in humans and have been document-
JAVMA, Vol 246, No. 1, January 1, 2015
ed, albeit to a lesser extent, in dogs as well. In hu-
mans, major age-related changes include decreases
in pulmonary elasticity, respiratory muscle strength,
and chest wall compliance.67 Alterations in pulmonary
immune cell number and function, reduced diffusing
capacity across the alveolar-capillary membrane, and
dysfunction in pulmonary β-adrenoreceptors and air-
way reactivity have also been associated with aging in
humans.68
Similar changes are considered likely to develop
with advancing age in dogs. Pulmonary alveoli enlarge
and coalesce, leading to reduced lung elasticity and
decreased surface area for gas exchange.69 In addition,
control of breathing has been shown to be altered with
age in dogs, with decreases in ventilation and responses
to hypoxia during slow-wave sleep.70
For the most part, even with this decrease in criti-
cal ventilatory functions, the respiratory system of
older humans is capable of maintaining adequate gas
exchange,71 and the same appears to be true for older
dogs.
Renal and Urinary Tract Changes
Although a gradual decline in renal function is nor-
mal in older animals, a substantial loss of functioning
nephrons must occur before changes in renal function
become evident by routine assessment. With the excep-
tion of acute renal damage, most damage that occurs
in the kidneys as dogs age is irreversible, and the heal-
ing of irreversibly damaged nephrons occurs by means
of replacement fibrosis.72,73 Renal histopathologic
preparations usually show some combination of a loss
of tubules with replacement fibrosis and mineraliza-
tion, glomerulosclerosis and glomerular atrophy, and
foci of mononuclear cells (small lymphocytes, plasma
cells, and macrophages) within the interstitium. These
changes are nonspecific, and as a result, the underlying
cause of the renal damage is usually unknown. Com-
pensatory hypertrophy occurs in the remaining viable
nephrons and creates a large functional reserve early on
in the process.
A study74 conducted over a period of 13 years eval-
uated clinical changes in renal function associated with
age in Beagles. Results showed that nephrosclerosis was
the most frequently diagnosed kidney lesion in older
dogs. The data from that study also indicated that nor-
mal kidney aging may lead to nephron loss of up to
75% before clinical signs or conventional biochemical
changes occur in older dogs. Animals with < 75% loss
may be more susceptible to renal insult than younger
animals still possessing renal reserve capacity.
Alterations in renal cortical and medullary GAGs
are also seen in aging dogs. Glycosaminoglycans are
among the most highly negatively charged molecules
known, and their presence in the glomerular basement
membrane helps maintain the membrane’s charge bar-
rier properties, which prevent protein from crossing
from the glomerulus into the glomerular filtrate.75 Hy-
aluronic acid in the extratubular stroma of the medulla
contributes a gelatinous support for the tubular struc-
ture of the nephron and may slow translocation of so-
dium in the renal tubules. One study75 evaluated GAG
composition of the renal cortex and medulla in healthy
JAVMA, Vol 246, No. 1, January 1, 2015
younger and older dogs. Results showed a significant
reduction in the heparan sulfate content of the cortex
(where all glomeruli are located) and a decline in hy-
aluronic acid content in the medulla in aging dogs. In
the renal cortex, heparan sulfate concentration, which
is the predominant GAG, gradually increased until the
sixth year of age and then sharply decreased as dogs
grew older. Heparan sulfate and hyaluronic acid were
present in equal proportions in renal cortexes of 1-
and 3-year-old dogs; however, in the renal cortexes of
10-year-old dogs, heparan sulfate formed only 30% of
the total GAG content, which is only 0.75 times the
hyaluronic acid content. The reason for the alterations
in the GAG composition in the renal cortex as dogs age
is not clear, but it may explain the frequency of pro-
teinuria related to aging in dogs. In the renal medulla,
chondroitin sulfate concentration, which forms a small
proportion of the total GAGs, remained unaltered in
young versus aging dogs. However, medullary hepa-
ran sulfate concentration, which formed a third of the
total GAG content in 1- and 3-year-old dogs, steadily
decreased as dogs aged. By 10 years of age, heparan sul-
fate formed only 14% of the total GAG content, and
the ratio of hyaluronic acid to heparan sulfate, which
is approximately 1.0 in younger dogs, increased to 3.9
in aging dogs.
Changes to the Endocrine System
Age-related alterations in adrenal cortex secretion,
serum cortisol and aldosterone concentrations, and
HPA axis regulation have been reported in dogs.76–78
Breed, dietary habits, and the level of physical activ-
ity can influence adrenal and renal parameters as well
as serum electrolyte concentrations and arterial blood
pressure.79 In addition, sex-related differences and hor-
mone cycle influences in healthy older dogs have been
reported.80
The influence of aging on adrenal responsiveness
in dogs has been well studied, with studies77,78,81 show-
ing that aging is associated with increased HPA activity,
characterized by increased plasma ACTH and cortisol
concentrations and increased urinary cortisol excre-
tion. Strasser et al78 theorized that increased cortisol
concentration could point to an “age-related hyperad-
renocorticism and indicates a reduced stress resistance
in older animals to equal stress than younger animals.”
Other authors have assumed that sensitivity to negative
glucocorticoid feedback at the pituitary, hypothalamus,
and hippocampus levels is reduced in aging dogs.77
Basal activity of the HPA axis is controlled by miner-
alocorticoid receptors (predominantly located in the
hippocampus) and glucocorticoid receptors (located
in the pituitary gland and the hippocampus). The loss
of mineralocorticoid and glucocorticoid binding sites
with aging may explain the altered feedback regulation
documented in elderly dogs. Healthy dogs between 11
and 14 years of age had a marked reduction in miner-
alocorticoid receptor-binding capacity (expressed as a
percentage of the corresponding levels in dogs between
18 and 24 months of age) in the dorsal hippocampus,
ventral hippocampus, septum, and hypothalamus.77
The effects of advancing age on serum concentra-
tions of T4 and TSH, on T4 responses to TSH, and on
Vet Med Today: Reference Point 71
TSH responses to thyrotropin-releasing hormone have
been studied in prepubertal, adult, middle-aged, and
old Beagles.82 Serum T4 concentrations were highest in
puppies and decreased by 40% in older dogs.82 A lon-
gitudinal study completed over the lifetime of healthy
Labrador Retrievers identified age-related decreases
in total triiodothyronine (T3), T4, and free T4 concen-
trations and age-related increases in T4 autoantibody
concentration.83 Baseline serum T4 concentration is
lower in some breeds, most notably sight hounds such
as Greyhounds84 and northern breeds such as Siberi-
an Huskies. Thus, a serum total T4 concentration that
is less than the lower reference limit can be a normal
age- or breed-related phenomenon and should not be
misinterpreted as evidence of hypothyroidism. In dogs,
serum T4 concentration can also be suppressed by a va-
riety of factors, including nonthyroidal illness and ad-
ministration of medications such as prednisone, pheno-
barbital, and sulfonamide antimicrobials.85 The reasons
for the reduction in T4 concentrations in older dogs are
not well-understood, and this decrease could be relat-
ed to decreased responsiveness of the thyroid gland to
TSH, fibrosis or atrophy of the thyroid gland, decreased
biological activity of TSH, and concurrent illness.
The pancreas and pancreatic function may also be
affected by age. Age is a significant risk factor for glucose
intolerance and diabetes mellitus in dogs. This may result
from either a reduction in the number of insulin recep-
tors or development of insulin receptor insensitivity.86 In
addition, the change in body fat content that is associ-
ated with aging is strongly and positively correlated with
changes in glucose tolerance. This reduction in insulin
sensitivity may be ameliorated through weight loss or
the prevention of becoming overweight.87 Improved glu-
cose tolerance has been demonstrated with diet restric-
tion in Labrador Retrievers undergoing a lifetime food
restriction trial.83 A 25% reduction in food intake over
the course of the dogs’ lives was associated with lower
mean basal serum glucose concentration (9% lower) and
plasma insulin concentration (33% lower) among the
dogs that were food restricted, compared with values for
their control-fed littermates.
There is also evidence that ovarian (endogenous
estrogen) status contributes to healthy aging.88 Female
Rottweilers tend to outlive male Rottweilers. However,
ovary removal during the first 4 years of life abolished
the female Rottweilers’ survival advantage.
Immune System Changes
The immune system is an interactive network of
cells, proteins, and signaling molecules designed to
provide protection from environmental pathogens, par-
asites, malignant cells, allergens, and toxins.89 Similar
to changes reported in rodents and humans,90 the im-
mune system in dogs undergoes complex remodeling
with advanced age, also known as immunosenescence.
Canine immunosenescence has been studied for more
than 3 decades,91 and various changes in the immune
system can be found in healthy aged dogs (Appendix).
There are fundamental changes in both T-cell– and
B-cell–mediated immunity in aging dogs. It is well-
documented that old dogs (8 to 13 years of age) have
lower lymphocyte proliferative response to specific an-
72 Vet Med Today: Reference Point
tigens, including phytohemagglutinin, concanavalin
A, and pokeweed mitogens, compared with responses
in young dogs (2 to 4 years of age).92–95 A study96 of
immune activation of lymphocytes in 40 young (< 1.5
years of age) and old (> 7 years of age) Fox Terriers
and Labrador Retrievers found that both breeds dem-
onstrated an age-related decrease in their ability to re-
spond to various mitogens, but that the decrease was
greater for Fox Terriers than for Labrador Retrievers.
Aging is also associated with changes in the distri-
bution of lymphocyte subsets in the peripheral blood,
including phenotypic changes in the absolute number,
relative percentage, or ratio of T cells and T-cell subsets
and B cells in the peripheral blood or in the expression
of surface markers of activation or memory in these
subpopulations.84,92,93,97–101
Age-associated changes in humoral immunity are
reflected in the number and function of B cells and
through antibody responses to antigens or vaccina-
tion.92,94–96 Increasing age has been associated with in-
creased production of inflammatory mediators in mice
and humans.102,103 The T-helper 1-to-T-helper 2 ratio
changes to reflect a dominance of the T-helper 1 sub-
population in the peripheral blood as dogs age.104 There
is also evidence of no significant changes in tumor ne-
crosis factor-α activity and increased interleukin-1–like
activity in older female dogs (age range, 8 to 13 years).95
On the other hand, the innate immune system is
apparently less vulnerable to age, compared with the
acquired immune system. There are subtle or no chang-
es in natural killer cell activity and polymorphonuclear
leukocyte phagocytic activity with age.94,95,105
Conclusions
It is readily apparent that considerable changes oc-
cur in virtually every body system of dogs with advanc-
ing age. Some of these changes can greatly affect the
health and well-being of older dogs and have a tremen-
dous impact on their owners, both from the standpoint
of cost of management and from the viewpoint of the
daily pet-owner relationship. An appreciation of aging
in dogs is critical for both clinical and research reasons.
In this regard, it is imperative to be able to distinguish
between what should be considered normal versus un-
healthy aging changes. This distinction would clearly
impact clinical management of aging dogs in that man-
agement could be adjusted on the basis of normal ag-
ing expectations. Research efforts in dogs could be fo-
cused on evaluating the effects of various interventions
in healthy aging dogs and older dogs with evidence of
disease. Additional effort is needed to define the clinical
assessments required to differentiate healthy aging from
disease for each of the systems identified.
a. Hutchinson D, Sutherland-Smith J, Watson AL, et al. Waltham Centre
for Pet Nutrition, Leicestershire, England: Unpublished data, 2012.
References
1. Goldston RT. Introduction and overview of geriatrics. In:
Goldston RT, Hoskins JD, eds. Geriatrics and gerontology of the
dog and cat. Philadelphia: WB Saunders Co, 1995;1–8.
2. AVMA. Total pet ownership and pet population. In: US pet ownership
and demographics sourcebook. Schaumburg, Ill: AVMA, 2007;6–23.
JAVMA, Vol 246, No. 1, January 1, 2015
3. P&G pet care consumer survey. Mason, Ohio: The Iams Com-
pany, P&G, 2011.
4. Brace JJ. Theories of aging. Vet Clin North Am Small Anim Pract
1981;11:811–814.
5. Deeb BJ, Wolf ND. Studying longevity and morbidity in large
and small breeds of dogs. Vet Med 1994;89:702–713.
6. Patronek GJ, Waters DJ, Glickman LT. Comparative longevity
of pet dogs and humans: implications for gerontology research.
J Gerontol Biol Sci Med Sci 1997;52:171–178.
7. Galis F, Van der Slujs I, Van dooren TJM, et al. Do large dogs die
young? J Exp Zool B Mol Dev Evol 2007;308:119–126.
8. Waters DJ. Aging well: how the science of aging informs
the practice of wellness, in Proceedings. North Am Vet Conf
2008;4–7.
9. Sharma R. Theories of aging. In: Timiars PS, ed. Physiologi-
cal basis of aging and geriatrics. Boca Raton, Fla: CRC Press,
1994;37–46.
10. Harman D. Aging, a theory based on free radical and radiation
chemistry. J Gerontol 1956;11:298–300.
11. Beckman KB, Ames BN. The free radical theory of aging ma-
tures. Physiol Rev 1998;78:547–581.
12. Landsberg G. Therapeutic agents for the treatment of cognitive
dysfunction syndrome in senior dogs. Prog Neuropsychopharma-
col Biol Psychiatry 2005;29:471–479.
13. Landsberg G, Araujo JA. Behavior problems in geriatric pets. Vet
Clin North Am Small Anim Pract 2005;35:675–698.
14. Landsberg GM, Nichol J, Araujo JA. Cognitive dysfunction syn-
drome: a disease of canine and feline brain aging. Vet Clin North
Am Small Anim Pract 2012;42:749–768.
15. Studzinski CM, Araujo JA, Milgram NW. The canine model of
human cognitive aging and dementia: pharmacological valid-
ity of the model for assessment of human cognitive-enhancing
drugs. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:489–
498.
16. Tapp PD, Siwak CT. The canine model of human brain aging:
cognition, behavior, and neuropathology. In: Conn PM, ed.
Handbook of models of human aging. New York: Academic Press,
2006;415–434.
17. Dimakopoulos AC, Mayer RJ. Aspects of neurodegeneration in
the canine brain. J Nutr 2002;132:1579S–1582S.
18. Head E. Neurobiology of the aging dog. Age (Dordr) 2011;33:
485–496.
19. Head E, Moffat K, Das P, et al. Beta-amyloid deposition and tau
phosphorylation in clinically characterized aged cats. Neurobiol
Aging 2005;26:749–763.
20. Araujo JA, Studzinski CM, Milgram NW. Further evidence for
the cholinergic hypothesis of aging and dementia from the ca-
nine model of aging. Prog Neuropsychopharmacol Biol Psychiatry
2005;29:411–422.
21. Araujo JA, Nobrega JN, Raymond R, et al. Aged dogs dem-
onstrate both increased sensitivity to scopolamine and de-
creased muscarinic receptor density. Pharmacol Biochem Behav
2011;98:203–209.
22. Head E, Liu J, Hagen TM. Oxidative damage increases with
age in a canine model of human brain aging. J Neurochem
2002;82:375–381.
23. Rofina JE, Singh K, Skoumalova-Vesela A, et al. Histochemical
accumulation of oxidative damage products is associated with
Alzheimer-like pathology in the canine. Amyloid 2004;11:90–
100.
24. Muler GH, Kirk RW, Scott DW. Small animal dermatology. 3rd
ed. Philadelphia: WB Saunders Co, 1983.
25. Case LP, Daristotle L, Hayek MG, et al. Canine and feline nutri-
tion. 3rd ed. Maryland Heights, Mo: Elsevier, 2011;265.
26. Villamil JA, Henry CJ, Bryan JN, et al. Identification of the most
common cutaneous neoplasms in dogs and evaluation of breed
and age distributions for selected neoplasms. J Am Vet Med Assoc
2011;239:960–965.
27. Zoran DL. Obesity in dogs and cats: a metabolic and endocrine
disorder. Vet Clin North Am Small Anim Pract 2010;40:221–239.
28. Mosier JE. Effect of aging on body systems of the dog. Vet Clin
North Am Small Anim Pract 1989;19:1–12.
29. Armstrong PJ, Lund EM. Changes in body composition and en-
ergy balance with aging. Vet Clin Nutr 1996;3:83–87.
JAVMA, Vol 246, No. 1, January 1, 2015
30. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al. Sarcopenia: Euro-
pean consensus on definition and diagnosis: report of the Euro-
pean Working Group on sarcopenia in older people. Age Ageing
2010;39:412–423.
31. Lang T, Streeper T, Cawthon P, et al. Sarcopenia: etiology, clini-
cal consequences, intervention and assessment. Osteoporos Int
2010;21:543–559.
32. Wannemacher RW, McCoy JR. Determination of optimal dietary
protein requirements of young and old dogs. J Nutr 1966;88:66–
74.
33. Venn MF. Variation of chemical composition with age in human
femoral head cartilage. Ann Rheum Dis 1978;37:168–174.
34. Roughley PJ. Changes in cartilage proteoglycan structure during
aging: origin and effects—a review. Agents Actus 1986;18(sup-
pl):19–29.
35. Davidson MG, Nelms SR. Diseases of the canine lens and cata-
ract formation. In: Gelatt KN, ed. Veterinary ophthalmology. 4th
ed. Ames, Iowa: Blackwell, 2007;859–887.
36. Colitz CMH, Bomser JA, Kusewitt DF. The endogenous and ex-
ogenous mechanisms for protection from ultraviolet irradiation
in the lens. Int Ophthalmol Clin 2005;45:141–155.
37. Shimada A, Ebisu M, Morita T, et al. Age-related changes in the
cochlea and cochlear nuclei of dogs. J Vet Med Sci 1998;60:41–48.
38. Overall KL. That dog is smarter than you know: advances in
understanding canine learning, memory, and cognition. Top
Companion Anim Med 2011;26:2–9.
39. Salvin HE, McGrath C, McGreevy PD, et al. Development of a
novel paradigm for the measurement of olfactory discrimination
in dogs (Canis familiaris): a pilot study. J Vet Behav 2012;7:3–10.
40. Wilson RS, Schneider JA, Arnold SE, et al. Olfactory identifica-
tion and incidence of mild cognitive impairment in older age.
Arch Gen Psychiatry 2007;64:802–808.
41. Hirai T, Kojima S, Shimada A, et al. Age-related changes in
the olfactory system of dogs. Neuropathol Appl Neurobiol
1996;22:531–539.
42. Wilson RS, Arnold SE, Schneider JA, et al. The relationship be-
tween cerebral Alzheimer’s disease pathology and odor identifi-
cation in old age. J Neurol Neurosurg Psychiatry 2007;78:30–35.
43. Wesson DW, Levy E, Nixon RA, et al. Olfactory dysfunction cor-
relates with amyloid-α burden in an Alzheimer’s disease mouse
model. J Neurosci 2010;30:505–514.
44. Hou Y, White RG, Bobik M, et al. Distribution of β-amyloid in
the canine brain. Neuroreport 1997;8:1009–1012.
45. Overall KL, Arnold SE. Olfactory neuron biopsies in dogs: a fea-
sibility pilot study. Appl Anim Behav Sci 2007;105:351–357.
46. Harvey CE, Shofer FS, Laster L. Association of age and body
weight with periodontal disease in North American dogs. J Vet
Dent 1994;11:94–105.
47. Gioso MA, Shofer F, Barros PS. Mandible and mandibular first
molar tooth measurements in dogs: relationship of radiographic
height to body weight. J Vet Dent 2001;18:65–68.
48. Kearns RJ, Hayek MG, Sunvold GD. Microbial changes in aged
dogs. In: Reinhart GA, Carey DP, eds. Recent advances in ca-
nine and feline nutrition. Vol II. 1998 Iams Nutrition Symposium.
Wilmington, Ohio: Orange Frazer Press, 1998;337–351.
49. Benno Y, Nakao H, Uchida K, et al. Impact of the advances in
age on the gastrointestinal microflora of Beagle dogs. J Vet Med
Sci 1992;54:703–706.
50. Gomes MO, Beraldo MC, Putarov TC, et al. Old Beagle dogs
have lower faecal concentrations of some fermentation prod-
ucts and lower peripheral lymphocyte counts than young adult
beagles. Br J Nutr 2011;106(suppl 1):S187–S190.
51. Sheffy BE, Williams AJ, Zimmer JF, et al. Nutrition and metabo-
lism of the geriatric dog. Cornell Vet 1985;75:324–347.
52. Buffington CA, Branam JE, Dunn GC. Lack of effect of age on
digestibility of protein, fat and dry matter in Beagle dogs. In:
Burger IH, Rivers JPW, eds. Nutrition of the dog and cat. Waltham
Symposium #7. Cambridge, Mass: Cambridge University Press,
1989;397.
53. Taylor EJ, Adams C, Neville R. Some nutritional aspects of age-
ing in dogs and cats. Proc Nutr Soc 1995;54:645–656.
54. Harper EJ. Changing perspectives on aging and energy require-
ments: aging and digestive function in humans, dogs and cats.
J Nutr 1998;128:2632S–2635S.
Vet Med Today: Reference Point 73
55. Brogna A, Loreno M, Catalano F, et al. Radioisotopic assessment
of gastric emptying of solids in elderly subjects. Aging Clin Exp
Res 2006;18:493–496.
56. Sweet MA, Ntambi JA, Gaumnitz EA, et al. Neuropeptide Y- and
peptide YY-containing colonic cells increase with ageing in male
rats. Neuropeptides 1996;30:385–390.
57. Biagi E, Nylund L, Candela M, et al. Through ageing, and be-
yond: gut microbiota and inflammatory status in seniors and
centenarians. PLoS ONE 2010;5:e10667.
58. Schmucker DL. Age-related changes in liver structure and func-
tion: implications for disease? Exp Gerontol 2005;40:650–659.
59. Kil DY, Vester Boler BM, Apanavicius CJ, et al. Age and diet
affect gene expression profiles in canine liver tissue. PLoS ONE
2010;5:e13319.
60. Laugier R, Bernard JP, Berthezene P, et al. Changes in pancreatic
exocrine secretion with age: pancreatic exocrine secretion does
decrease in the elderly. Digestion 1991;50:202–211.
61. Anand BS, Vij JC, Mac HS, et al. Effect of aging on the pancreatic
ducts: a study based on endoscopic retrograde pancreatography.
Gastrointest Endosc 1989;35:210–213.
62. Gullo L, Ventrucci M, Naldoni P, et al. Aging and exocrine pan-
creatic function. J Am Geriatr Soc 1986;34:790–792.
63. Bright JM, Mears E. Chronic heart disease and its management.
Vet Clin North Am Small Anim Pract 1997;27:1305–1329.
64. Strasser A, Simunek M, Seiser M, et al. Age-dependent changes
in cardiovascular and metabolic responses to exercise in Beagle
dogs. Zentralbl Veterinarmed A 1997;44:449–460.
65. Templeton GH, Platt MR, Willerson JT, et al. Influence of aging
on left ventricular hemodynamics and stiffness in Beagles. Circ
Res 1979;44:189–194.
66. Schober KE, Fuentes VL. Effects of age, body weight, and heart
rate on transmitral and pulmonary venous flow in clinically
normal dogs. Am J Vet Res 2001;62:1447–1454.
67. Dyer C. The interaction of ageing and lung disease. Chron Respir
Dis 2012;9:63–67.
68. Sharma G, Goodwin J. Effect of aging on respiratory system
physiology and immunology. Clin Interv Aging 2006;1:253–260.
69. Mauderly JL. Effect of age on pulmonary structure and function of
immature and adult animals and man. Fed Proc 1979;38:173–177.
70. Phillipson EA, Kozar LF. Effect of aging on metabolic respiratory
control in sleeping dogs. Am Rev Respir Dis 1993;147:1521–1525.
71. Janssens JP, Pache JC, Nicod LP. Physiological changes in re-
spiratory function associated with ageing. Eur Respir J 1999;
13:197–205.
72. Grauer GF. Early detection of renal damage and disease in dogs
and cats. Vet Clin North Am Small Anim Pract 2005;35:581–596.
73. Gonin-Jmaa D, Senior DF. The hyperfiltration theory: progres-
sion of chronic renal failure and the effects of diet in dogs. J Am
Vet Med Assoc 1995;207:1411–1415.
74. Kaufman GM. Renal function in the geriatric dog. Compend
Contin Educ Pract Vet 1984;6:108–109.
75. Vasan NS, Saporito RA Jr, Saraswathi S, et al. Alterations of renal
cortex and medullary glycosaminoglycans in aging dog kidney.
Biochim Biophys Acta 1983;760:197–205.
76. Reul JM, Rothuizen J, de Kloet ER. Age-related changes in the
dog hypothalamic-pituitary-adrenocortical system: neuroendo-
crine activity and corticosteroid receptors. J Steroid Biochem Mol
Biol 1991;40:63–69.
77. Rothuizen J, Reul JM, van Sluijs FJ, et al. Increased neuroendo-
crine reactivity and decreased brain mineralocorticoid receptor-
binding capacity in aged dogs. Endocrinology 1993;132:161–168.
78. Strasser A, Niedermüller H, Hofecker G, et al. The effect of
aging on laboratory values in dogs. Zentralbl Veterinarmed A
1993;40:720–730.
79. Guyton AC, Hall JE. The pituitary hormones and their control
by the hypothalamus. In: Guyton AC, Hall JE, eds. Textbook of
medical physiology. 10th ed. Philadelphia: WB Saunders Co,
2000;846–856.
80. Reimers TJ, Lawler DF, Sutaria PM, et al. Effects of age, sex, and
body size on serum concentrations of thyroid and adrenocorti-
cal hormones in dogs. Am J Vet Res 1990;51:454–457.
81. Goy-Thollot I, Decosne-Junot C, Bonnet JM. Influence of ag-
ing on adrenal responsiveness in a population of eleven healthy
Beagles. Res Vet Sci 2007;82:195–201.
74 Vet Med Today: Reference Point
82. Gonzalez E, Quadri SK. Effects of aging on the pituitary-thyroid
axis in the dog. Exp Gerontol 1988;23:151–160.
83. Lawler DF, Ballam JM, Meadows R, et al. Influence of lifetime
food restriction on physiological variables in Labrador Retriever
dogs. Exp Gerontol 2007;42:204–214.
84. Shiel RE, Brennan SF, Omodo-Eluk AJ, et al. Thyroid hormone
concentrations in young, healthy, pretraining Greyhounds. Vet
Rec 2007;161:616–619.
85. Daminet S, Ferguson DC. Influence of drugs on thyroid func-
tion in dogs. J Vet Intern Med 2003;17:463–472.
86. Davis PJ, David FB. Endocrinology and aging. In: Clinical
aspects of aging. Baltimore: Williams & Williams, 1983;396–
410.
87. Larson BT, Lawler DF, Spitznagel EL Jr. Improved glucose toler-
ance with lifetime diet restriction favorably affects disease and
survival in dogs. J Nutr 2003;133:2887–2892.
88. Waters DJ, Kengeri SS, Clever B, et al. Exploring mechanisms of
sex differences in longevity: lifetime ovary exposure and excep-
tional longevity in dogs. Aging Cell 2009;8:752–755.
89. Chandra RK. Basic immunology and its application to nutrition-
al problems. In: Forse RA, Bell S, Blackburn GL, et al, eds. Diet,
nutrition and immunity. Boca Raton, La: CRC Press, 1994;1–8.
90. Meydani SN, Hayek MG. Vitamin E and aging immune re-
sponse. Clin Geriatr Med 1995;11:567–576.
91. Gerber JD, Brown AL. Effect of development and aging on the
response of canine lymphocytes to phytohemagglutinin. Infect
Immun 1974;10:695–699.
92. HogenEsch H, Thompson S, Dunham A, et al. Effect of age
on immune parameters and the immune response of dogs to
vaccines: a cross-sectional study. Vet Immunol Immunopathol
2004;97:77–85.
93. Lawler DF, Larson BT, Ballam JM, et al. Diet restriction and age-
ing in the dog: major observations over two decades. Br J Nutr
2008;99:793–805.
94. Greeley EH, Kealy RD, Ballam JM, et al. The influence of age on
the canine immune system. Vet Immunol Immunopathol 1996;
55:1–10.
95. Strasser A, Teltscher A, May B, et al. Age-associated changes
in the immune system of German Shepherd Dogs. J Vet Med A
Physiol Pathol Clin Med 2000;47:181–192.
96. Kearns RJ, Hayek MG, Turek JJ, et al. Effect of age, breed and
dietary omega-6 (n-6):omega-3 (n-3) fatty acid ratio on immune
function, eicosanoid production, and lipid peroxidation in young
and aged dogs. Vet Immunol Immunopathol 1999;69:165–183.
97. Miller RA. Age-related changes in T cell surface markers: a lon-
gitudinal analysis in genetically heterogeneous mice. Mech Age-
ing Dev 1997;96:181–196.
98. Trzonkowski P, Debska-Slizień A, Jankowska M, et al. Immu-
nosenescence increases the rate of acceptance of kidney allo-
transplants in elderly recipients through exhaustion of CD4+
T-cells. Mech Ageing Dev 2010;131:96–104.
99. Ferguson FG, Wikby A, Maxson P, et al. Immune parameters in
a longitudinal study of a very old population of Swedish people:
a comparison between survivors and nonsurvivors. J Gerontol A
Biol Sci Med Sci 1995;50:B378–B382.
100. Wikby A, Maxson P, Olsson J, et al. Changes in CD8 and CD4
lymphocyte subsets, T cell proliferation responses and non-sur-
vival in the very old: the Swedish longitudinal OCTO-immune
study. Mech Ageing Dev 1998;102:187–198.
101. Faldyna M, Levá L, Knötigová P, et al. Lymphocyte subsets in
peripheral blood of dogs—a flow cytometric study. Vet Immunol
Immunopathol 2001;82:23–37.
102. Roubenoff R, Harris TB, Abad LW, et al. Monocyte cytokine pro-
duction in an elderly population: effect of age and inflamma-
tion. J Gerontol A Biol Sci Med Sci 1998;53:M20–M26.
103. Bruunsgaard H, Skinhøj P, Qvist J, et al. Elderly humans show
prolonged in vivo inflammatory activity during pneumococcal
infections. J Infect Dis 1999;180:551–554.
104. Horiuchi Y, Nakajima Y, Nariai Y, et al. Th1/Th2 balance in ca-
nine peripheral blood lymphocytes—a flow cytometric study.
Vet Immunol Immunopathol 2007;118:179–185.
105. Greeley EH, Ballam JM, Harrison JM, et al. The influence of age
and gender on the immune system: a longitudinal study in Lab-
rador Retriever dogs. Vet Immunol Immunopathol 2001;82:57–71.
JAVMA, Vol 246, No. 1, January 1, 2015
 Appendix
Summary of studies of immunosenescence in dogs.

Breed Mean age or age range (y) Findings

Fox Terrier96 11.5 Decreased mitogen responses to phytohemagglutinin, pokeweed mitogen,
Labrador Retriever96 9.6 and concanavalin A
Beagle, Labrador Retriever, 12.1
and other breeds92
Labrador Retriever93 Lifetime
Labrador Retriever94 9.1

German Shepherd Dog95 8–13 Decreased mitogen response to phytohemagglutin

Beagle, Labrador Retriever, 12.1 Higher CD8+, lower CD4+:CD8+
and other breeds92
Beagle101 >5 Higher CD8+, no change in CD4+, lower CD4+:CD8+, higher B cell

Labrador Retriever93 Lifetime Lower CD8+, higher B cell

Fox Terrier96 11.5 Decreased antibody response to sheep RBCs
Labrador Retriever96 9.6 No changes in antibody response to sheep RBCs
Labrador Retriever94 9.1 No changes in antibody response to protein antigen
German Shepherd Dog92 12.1 No changes in antibody response to vaccine; no difference in IgM and IgG

German Shepherd Dog95 8–13 No changes in IgG

German Shepherd Dog95
Beagle104
Labrador Retriever105
Labrador Retriever94
German Shepherd Dog95
8–13 Decreased interluekin-2, no changes in tumor necrosis factor-α, increased
interleukin-1–like activity in female dogs
>8 Inclined to T-helper 1 dominance
Lifetime No difference in NK cell activity and polymorphonuclear leukocyte phagocyte
activity
9.1 No difference in NK cell activity
8–13 No difference in polymorphonuclear leukocyte phagocytic activity and
increased NK cell activity in female dogs

NK = Natural killer.

JAVMA, Vol 246, No. 1, January 1, 2015 Vet Med Today: Reference Point 75

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