Using survey data, medical and family histories and blood samples of over 100 human participants in the Stanford-Ellison cohort, a long-term program begun 10 years to study the immunology of aging(1), has revealed a fundamental inflammatory mechanism associated with human aging and implicates this inflammatory process as a driver of cardiovascular disease and increased rates of mortality overall. Metabolites, or breakdown products, of nucleic acids — the molecules that serve as building blocks for our genes — circulating in the blood can trigger this inflammatory process, the study found.
The study also posits that caffeine and its own metabolites may counter the action of these circulating nucleic-acid metabolites, possibly explaining why coffee drinkers tend to live longer than abstainers. Caveat: the inflammatory mechanism was found to be activated only in some of the older study participants. Those in whom it was relatively quiescent tended to drink more caffeinated beverages. Laboratory experiments revealed that the mechanism was directly countered by caffeine and associated compounds.
For the new study, the researchers compared blood drawn from older versus younger study participants to see which genes tended to be more highly activated in older people. They zeroed in on two clusters of genes whose activity was associated with the production of a potent circulating inflammatory protein called IL-1-beta. The genes within each cluster appeared to work in coordination with one another.
The researchers also looked at two particular groups of older participants: One with high activation of one or both inflammatory gene clusters, and the other with one or both clusters exhibiting low activation. On reviewing these individuals’ medical histories, the scientists learned that nine of the 12 subjects with high cluster activity had high blood pressure, compared with only one of the 11 subjects with low cluster activity.
Mark Davis, PhD, a professor of microbiology and immunology and the director of the Stanford Institute for Immunity, Transplantation and Infection, said, “Our findings show that an underlying inflammatory process, which is associated with aging, is not only driving cardiovascular disease but is, in turn, driven by molecular events that we may be able to target and combat.”
Individuals in the “high” group were much more likely to have stiff arteries — a risk factor for cardiovascular complications — than those in the “low” group.
Furthermore, those in the low group were eight times as likely as those in the high group to report having at least one close family member who had lived to age 90 or older. Not only that, but participants in the high group who were older than 85 in 2008 were substantially more likely to have died by 2016 than were those in the low group. The high group’s blood also showed signs of increased activity of free radicals, which can harm cells, compared with the low group’s blood. The high group also had elevated concentrations of IL-1-beta, as well as of several nucleic-acid breakdown products that can be produced by free-radical action.
The researchers found that incubating a type of immune cell with two of those nucleic-acid metabolites boosted activity in one of the gene clusters, resulting in increased IL-1-beta production. When injected into mice, the substances triggered massive systemic inflammation, along with high blood pressure. In addition, immune cells infiltrated and clogged the animals’ kidneys, increasing renal pressure substantially.
(1) In that program, healthy participants ages 20-30 and another group older than 60 were monitored annually via surveys, blood draws and reviews of their medical histories.