Transposable elements in the genome are capable of hijacking cellular machinery to copy themselves into new locations in the genome. Many of these sequences are clearly the remnants of ancient infections by retroviruses, degraded and disabled by millions of years of evolutionary mutational change. In other cases, the origin is less clear. An infectious retrovirus arriving from the environment copies its own genetic material into the genome in order to replicate. Alteration of the genome by retroviral infection and unfettered activation of transposable elements is both a cause of pathology and an important mechanism of evolutionary change. It has been going on for a long time: a sizable fraction of any given mammalian genome is made up of transposable elements.
Transposable elements, including the genetic remains of ancient retroviruses, are repressed in youth. These sequences are packaged away in compact DNA and hidden from transcriptional machinery. Aging brings changes to the epigenetic control of the structure of DNA, however. Transposable elements begin to be exposed, allowing replication to cause genetic damage. Perhaps worse, the engagement of the machinery of gene expression with retroviral transposable elements can produce molecules that the immune system recognizes as foreign, in some cases appearing similar to viral particles. This provokes harmful inflammation, disruptive to cell and tissue function.
It was recently noted that expression of the transposable element human endogenous retrovirus K (HERVK) increases with age and can be implicated in age-related inflammation and an increased burden of cellular senescence. This is one of many lines of evidence in support of significant harm arising from a greater activation of transposable elements in later life. Importantly, inhibiting the activity of HERKV and analogous retroviruses reduces the burden of cellular senescence and slows aging in animal models. Today's open access paper is interesting to read in this context, as the authors look at the capacity of the immune system in human study participants to recognize HERVK retroviral particles, and find that a greater capacity correlates with survival to very old age. That said, one should bear in mind that it requires only a small reduction in mortality risk for specific gene variants to appear significantly more often in older people.
Immunogenetics of longevity and its association with human endogenous retrovirus K
The human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality.
We utilized high-resolution genotyping to characterize HLA and in a large sample (N = 986) of participants ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. We determined in silico the median predicted binding affinity for each individual and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW).
The analyses yielded only one statistically significant effect - namely, a positive association between age and HERVK. Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses. Taken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.
View the full article at FightAging
