Age-Related Decline in Thymic Activity Correlates with Life Span in Dog Breeds

Researchers here report on thymic activity in dog breeds of varying longevity. The thymus plays an important role in the creation of new T cells, but its activity declines with age, most notably in early adulthood via the process of thymic involution, but then further in later life. A lower supply of new immune cells contributes to the age-related decline of the immune system, which is in part a structural problem of too many memory T cells dedicated to specific pathogens and too few naive T cells capable of dealing with new threats. Those threats are not just invading microorganisms, but also harmful senescent and cancerous cells. The progressive failure of the immune system is one of the reasons why cancer is an age-related condition and the number of senescent cells increase with age. It isn't just a matter of increasing frailty due to vulnerability to infection, as immune decline also influences many other aspects of aging. Given all of this, there is some interest in rejuvenation of the thymus, restoring it to youthful levels of activity. Possible approaches here include engineering of thymus tissue for transplantation, or manipulation with signal molecules that direct thymic growth and function.

With increasing age, there is a gradual deterioration in immune function, leading to a reduced response to infectious agents and vaccination, alongside an increase in prevalence of autoimmune and neoplastic diseases. A similar age-related decline in health is seen comparing humans and companion animals. Intimately linked with the decline in immune function is the age-associated regression of the thymus. Since thymic involution is seen in all mammalian species, this has led to the suggestion that immunosenescence, associated with a decline in thymic output, is an evolutionary conserved event. Thus, identifying the features of immunosenescence in companion animals represents an opportunity for comparative and translational research into how immune function declines with age.

Thymic involution is associated with a progressive decline in T cell output to the peripheral lymphocyte pool and as a consequence, expansion of existing memory T cell populations can take place. However, this might lead to reduced diversity in the T cell repertoire and impairment of immune responses to novel antigens, for example during infection or vaccination. Preservation of immunity is a major contributory factor for maintaining health into old age and although there is evidence for an association between thymic output and longevity, many of these experiments have been performed in inbred or genetically-modified laboratory rodents, which might not reflect the situation in humans. Whilst thymic size may be an indicator of immunocompetence/immunosenescence in mammals it is not easily measured clinically. Evaluation of thymic output in terms of the presence of recent thymic emigrants (RTE) in peripheral blood might be an acceptable surrogate marker.

During T cell development in the thymus, the T cell receptor δ gene segments are excised and form a signal joint T cell receptor excision circle (sj-TREC). Since its formation occurs specifically in the thymus and this DNA does not replicate, sj-TREC has been used as a marker for RTEs in peripheral blood samples. In humans and mice, real-time qPCR has been employed, showing an age-associated decline in sj-TREC values in blood, suggesting a reduction in the number of RTEs with increasing age. However, sj-TRECs are still detectable, even in some very elderly humans, suggesting that thymic output can be maintained into old age in some individuals. A recent study has demonstrated that sj-TRECs can be measured in companion animals. Studies in pedigree dogs have demonstrated that there are breed-related differences in longevity, the rate of aging, and susceptibility to diseases associated with aging. Such differences in longevity suggest that there are likely to be breed effects/genetic factors influencing the aging process that might impact on the onset of immunosenescence. The aim of the present study was to develop a real-time qPCR assay to measure sj-TRECs in canine blood samples and to examine how age and breed influence sj-TREC values in dogs.

When sj-TREC values were assessed in Labrador retriever dogs, normalized against either lymphocyte counts or albumin expression, an age-associated decline was identified in both instances. The greatest decline occurred between the ages of 1 and 5 years, which suggests the largest reduction in thymic output occurs between reaching sexual maturity and early middle age in the canine species. A similar trend is seen in humans, where thymic output remains relatively high until the teenage years, when it begins to decline rapidly, with the greatest decline in sj-TRECs having occurred by middle age, between 40 and 50 years old. After reaching 5 years of age, canine sj-TREC values were found to stabilise, with a mean value approximately 20% of that seen in dogs younger than 1 year old, before declining further at around 9 years of age. In older humans, sj-TREC values show a slow decline between the 6th and 9th decades of life before decreasing significantly in the 10th decade. sj-TRECs were undetectable in many mature and geriatric dogs, suggesting that thymic output in these dogs is very low or that production of naïve T-cells has ceased. However, this was not the case in all dogs of a similar age, suggesting that some individuals can maintain thymic output into old age, which is similar to that reported in human studies.

Breed influences on sj-TREC were investigated by studying two groups that represent the extremes of the canine lifespan spectrum; small breed dogs with a relatively long life expectancy and large breed dogs with a relatively short life expectancy. Studies in humans have proposed an association between maintenance of thymic function and lifespan and have suggested that sj-TREC analysis might be of use as a biomarker for determining longevity. Both groups demonstrated a similar age-related decline in sj-TREC, with the greatest reduction occurring between young adulthood and middle age. However, the onset of the decline in sj-TRECs was found to occur at an earlier age in the short-lived breeds compared with the long-lived breeds, suggesting that thymic involution might occur prematurely in the former. Furthermore, some individuals of short-lived breeds were identified that had undetectable sj-TREC as young as 2 years of age, compared with the other breeds assessed, where this did not occur until around 4-5 years of age. Therefore, if thymic involution is occurring at an earlier biological time point in some dog breeds, this might have an impact on their subsequent lifespan/healthspan. This is consistent with a recent study in which there was a strong relationship between lifespan, body size and rate of aging, with the largest breeds also having evidence of an earlier onset of the aging process.



It would be much more interesting to see the Dog Aging Project perform an intervention like using temporary gene therapy to regrow the thymus rather than their current experiment of simply giving dogs rapamycin (probably a poor calorie restriction mimetic).

Posted by: Jim at November 14th, 2016 1:11 PM

@Bill Sardi: Those are review articles, and none of them gives results showing that zinc supplementation can reverse the age-related decline in thymic function in humans without frank zinc deficiency, let alone that it can reverse thymic involution. See here for a review discussing the lack of evidence supporting that conclusion, starting with "In contrast to the relatively clear association of zinc deficiency with impaired immune function, the beneficial effects of zinc supplementation on immune response has not been demonstrated in a consistent manner, particularly in human studies."

Posted by: Michael at November 22nd, 2016 2:09 PM

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