Longer-Lived Mice Better Resist Immune System Decline
In this open access paper, researchers examine the functionality of the immune system in old mice. They find a correlation between greater longevity and more successful compensation for age-related changes. Longer-lived mice tend to have immune systems capable of better, less disrupted function in later life. Given the importance of the immune system to many aspects of tissue function, over and above its role in defending against pathogens, this should perhaps not be all that surprising. Open questions remain on the relevant mechanisms and the degree to which sustained immune performance is a matter of resisting damage versus better compensating for damage versus stochastic differences in the load of molecular damage between individuals.
Aging of the immune system, which is known as immunosenescence, involves a striking rearrangement of almost every component, leading to changes including enhanced as well as diminished functions. In addition, the functioning of the immune system has been demonstrated to be an excellent marker of health, given that several age-related changes in immune functions are predictive of mortality and lifespan. Thus, long-lived individuals seem to exhibit a high degree of preservation of several functions of the immune system with values similar to those observed in adult individuals. This may be essential to reach a very advanced age in a healthy condition.
Among all the age-related changes that the immune system undergoes, the most obvious is the involution of the thymus gland. Accordingly, one of the most marked age-related alterations in the immune cells has been reported in the T lymphocytes, specifically in the lymphoproliferative response to mitogens, which is decreased in old subjects for both humans and experimental animals. The study of the proliferative response of leukocytes to a given stimulus has become an important issue given that a low lymphoproliferative response to mitogens has been linked to an increased mortality, and together with other parameters, defines the immune risk phenotype in humans.
Cytokines are principal mediators of interactions among immune cells. They are responsible for the development and resolution of immune response and are greatly affected by the aging process. In fact, an age-related loss of homeostasis in cytokine networks can contribute significantly to health impairment in old age. In this context, together with the previously mentioned age-related loss of functionality in immune cells, aging is characterized by a chronic low-grade inflammatory status, so-called "inflammaging". Thus, it has been described that an age-related increase in release of pro-inflammatory cytokines in resting cells leads to a sterile inflammation. This is accompanied by an elevation of circulating levels of cytokines in old subjects, such as IL-6, which in addition has been related to a higher risk of mortality. However, cells from old subjects produce lower pro-inflammatory cytokines when needed to do so, i.e., after a mitogenic stimulus, compared to those of adult subjects. Again, long-lived individuals, despite having high levels of pro-inflammatory markers, have a postponed disease onset, making it difficult to understand whether "inflammaging" is beneficial or detrimental.
Based on the striking facts regarding lymphoproliferation and cytokine release by immune cells in long-lived individuals, it was hypothesized that these individuals could present different proliferative as well as cytokine release dynamics as an adaptive mechanism. Moreover, given that all the studies in long-lived individuals previously mentioned have been cross-sectional, it is still not known if they reach those advanced ages due to the maintenance of optimal immune cell function during their whole life (as if they were adults) or whether they experience an age-related impairment in these functions but are able to compensate for it. In order to address these questions, an individualized longitudinal study was performed on female ICR-CD1 mice analyzing the proliferation as well as the cytokine secretion profile of leukocytes obtained from animals at different ages. The study was performed starting at the adult age, 40 weeks old, and followed each animal individually until its death.
In the present study, it has been found that old mice exhibit a significant increase in the basal proliferation of immune cells, what takes place in the absence of a proliferative stimulus, with respect to when they were younger. In contrast, long-lived mice show basal proliferative levels similar to when they were adults. The high proliferation in the absence of stimulus seen in old mice implies a deregulation of the immune system. Those mice that naturally achieve high longevity are the ones that not only maintained lower levels of basal proliferation and higher levels of proliferation after stimulation during their whole lifetime, but are also those that achieve a better control of the effects of aging on the immune functions. Thus, long-lived mice are those that maintained a lower secretion of pro-inflammatory cytokines and a higher secretion of anti-inflammatory cytokines in unstimulated conditions as well as a higher one upon stimulation when they were old, compared to their age-matched counterparts. This is the first study to demonstrate that the animals reaching high longevity experience immune-senescent changes (to a lesser extent than those which do not reach advanced ages), but they are able to compensate for them by showing optimal levels when they are long-lived.
There is less inflammation if you have the good SNP's of IL6, specifically rs1800795 CC. It has shown longevity effects in Japan and other places. Also, it is beneficial to have ADA gene SNP allele CC of rs73598374, as it activates telomerase in leukocytes, which is needed to length telomeres, especially in the elderly. This SNP works together with the TNF gene SNP's rs1800629 GG and rs361525 GG alleles to lengthen Leukocyte telomeres (Napolioni, 2011). If you don't have the longevity alleles, perhaps in the future CTRISPR technology could give you the necessary alleles.