Because dogs share a large number of genetic diseases with man (Sutter and Ostrander 2004
) as well as common environments that may trigger disease, they present an excellent model system for the study of intrinsic diseases and the factors that predispose toward the diseased state. We have begun an in-depth study of the genetic basis of diseases associated with aging using gross autopsy and histopathology to define the state of health of a dog at death. We have chosen the Portuguese Water Dog as our model system to demonstrate the power of this approach.
These dogs present a picture of morphological (Table ) as well as histological (Table ) changes, many of which are correlated with age of death. Perhaps the most notable aspect we have observed is the large number of autopsies (exclusive of those with neoplasms) in which numerous histological changes are found that involve multiple organs or tissues (Table , Fig. ). As yet, we do not know if these are independent events or related to some underlying systemic change. However, several of the changes in different organs appear to be correlated (Table ) suggesting some common etiology. Additionally, we have identified clusters of pathological processes that point to a common denominator dependent on aging (Fig. ). Thus, in one cluster, we find traits that are characteristic of immune processes. Subacute and chronic inflammations are accompanied by plasmacytic and lymphocytic infiltration. The continued inflammatory process can result in either resolution or atrophy and fibrosis. With increasing age, incidents involving the immune system increase and result in accumulated damage across tissues or organs, an observation that aligns well with current concepts of the aging process (Cheville 1983
; Amenta et al. 1990
). The second cluster suggests that processes that lead to increased cell growth, adenomas, and hyperplasia are connected with iron storage. This association was unexpected. It is not surprising that factors giving rise to hyperplasias might also favor growth of benign tumors; however, the connection with hemosiderosis requires further exploration.
Several of the morphological and histological changes that we have observed appear to be heritable. In the PWD breed, two major IGF1
haplotypes are segregating (Chase et al. 2002
; Sutter et al. 2007
). Identification of these haplotypes led to the discovery that fixation of these two types differentiate large from small breeds of dogs (Sutter et al. 2007
). IGF1 has been implicated in regulating longevity in a number of organisms (Kenyon 2001
; Bartke 2005
), and genome comparisons between different dog breeds have demonstrated that IGF1, a major determinant of variation in size between breeds (Sutter et al. 2007
), also plays an important role in determining the difference in longevity between breeds (Jones et al. 2008
In a recent review, Rodriguez et al. (2007
) summarized much of the evidence implicating the IGF1 pathway in disease concluding that “The constellation of genes in this key pathway contains potential candidates in a number of complex diseases, including growth disorders, metabolic syndromes, diabetes, cardiovascular disease, central nervous system diseases, as well as longevity, aging and cancer.” Preliminary data, comparing genomes of dogs from large and small breeds (differentiated by their IGF1
haplotypes) demonstrated that the breed incidence of specific diseases could be associated with specific haplotypes of IGF1
(Chase et al. 2009
). Thus, the Portuguese Water Dog, as a model system, presents an unusual opportunity to assess the impact of IGF1
on disease and senescence.
As a preliminary analysis (Table ), we have examined the correlation of parameters of morphology and of histological change found at autopsy with the PWD IGF1
haplotype that is common to small breeds (Sutter et al. 2007
). Since small dogs live longer, and longer-lived dogs could have different frequencies and time courses of disease, there could be a potential bias in the correlations between the IGF1
small dog haplotype and various pathologies. However, there was no significant age effect for the small dog haplotype in our dataset (the mean age of death of PW dogs with no copy of the small dog haplotype was 10.73
0.71 years; with one copy 11.56
0.42 year; with two copies 11.44
The correlations between the “small dog” IGF-1 allele (FH2295) and various organ metrics or histological observations in specific tissues
The correlations in Table are only suggestive, given the number of traits tested and the somewhat low frequency of dogs homozygous for the small dog haplotype (18%). Because of the limited number of homozygotes in the current dataset, we could not analyze the correlations between age of death and specific pathologies within a specific genotype. Nevertheless, the analysis in Table is instructive.
As expected, all of the morphological traits are negatively correlated with the small dog haplotype—i.e., their weight or length becomes smaller with the presence of one to two copies of this haplotype. Many, but not all, of these traits also are negatively correlated with age. Most interesting is the finding that the length of the small intestine is inversely correlated with age of death (Table ). Although organs of IGF1 small-haplotype dogs may be smaller because of loss of mass with age, an alternative may be that those dogs with smaller organs are longer lived. This latter explanation would be more likely for the left medial lobe of the lung, the length of the small intestine and the tail, as well as the weight of the right kidney and the tongue. It is interesting to note that although the weight of the adrenals and the length of the trachea are positively correlated with age, they are negatively correlated with the small dog IGF1 haplotype that is associated with increased longevity. Data from other breeds should assist in clarifying the relationship of these two phenotypes to longevity.
There also is the suggestion in Table that several histological changes could prove to be associated with IGF1
as the database becomes more robust. Although the present state of the database makes it premature to draw conclusions, some relationships in Table are worthy of comment: many of the observed tissue changes are negatively correlated with the small dog IGF1
haplotype (i.e., fewer tissue changes may be associated with the increased longevity haplotype). In contrast to humans, atherosclerosis is not considered to be an important source of tissue infarct in the dog (Maxie 1993
; Robinson and Maxie 1993a
). As a result, the effects of IGF1
on these two histopathologies can be evaluated separately, and as can be seen in Table , they appear to respond differently to the small dog IGF1
haplotype, which appears to increase the risk of infarcts despite decreasing atherosclerosis. It is also interesting that the frequency of carcinomas is positively correlated to the small dog IGF1
haplotype, whereas the frequency of hemangiosarcomas is inversely correlated with this haplotype. MacEwen et al. (2004
) suggest the IGF1 receptor expression could regulate growth of different neoplasms, whereby those that express the receptor will respond to increased levels of IGF1 (inverse correlation with PWD small dog IGF1
haplotype). Previous studies of different rodent species concluded that distinct tumor suppressing mechanisms evolved in large, long-lived species as well as in small but long-lived species (Seluanov et al. 2008
). In purebred dogs, such evolution is confounded by selection during breeding, which combines genes from different, more ancient, breeds without allowing subsequent counter-selection that would offset ill effects in later life.
In this paper, we have presented a first report on the distribution of phenotypes that were encountered. Several of these appear to be heritable. However, the number of dogs autopsied will need to be greatly increased before identification of genetic loci will be possible. Nevertheless, evidence of heritability implies that such identification eventually will be possible. When that occurs, we may be able to identify loci associated with senescence, e.g., for the reduction in muscle mass that accompanies aging as well as for the changes in bone (osteoporosis) or thyroid (atrophy) that take place. Most importantly, we should be able to clarify the role that IGF1 plays in determining disease frequency and longevity in a large mammal.