Stanford University School of Medicine scientists have unearthed a connection between advancing age, systemic inflammation, cardiovascular disease and caffeine consumption.
Extensive analysis of blood samples, survey data and medical and family histories obtained from more than 100 human participants in a multiyear study has revealed a fundamental inflammatory mechanism associated with human aging and the chronic diseases that come with it.
The study, published online Jan. 16 in Nature Medicine, 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 provides evidence 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.
"More than 90 percent of all noncommunicable diseases of aging are associated with chronic inflammation," said the study's lead author, David Furman, PhD, a consulting associate professor at the Stanford Institute for Immunity, Transplantation and Infection. More than 1,000 papers have provided evidence that chronic inflammation contributes to many cancers, Alzheimer's disease and other dementias, cardiovascular disease, osteoarthritis and even depression, he said.
"It's also well-known that caffeine intake is associated with longevity," Furman said. "Many studies have shown this association. We've found a possible reason for why this may be so."
Mark Davis, PhD, a professor of microbiology and immunology and the director of the Stanford Institute for Immunity, Transplantation and Infection, shares senior authorship of the study with Benjamin Faustin, PhD, a cell biologist at the University of Bordeaux in France. Davis is also a Howard Hughes Medical Institute investigator.
"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," said Davis, who holds the Burt and Marion Avery Family Professorship.
Notably, this inflammatory mechanism was found to be activated only in some, but not all, 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.
The investigators made this discovery using data gathered from the Stanford-Ellison cohort, a long-term program begun 10 years ago by Davis and study co-author Cornelia Dekker, MD, professor of pediatric infectious diseases, to study the immunology of aging. 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.
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. Follow-up studies by study co-author Francois Haddad, MD, a clinical associate professor of cardiovascular medicine, revealed that 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.
Intrigued by the correlation between older participants' health, gene-cluster activation and self-reported rates of caffeine consumption, the researchers followed up and verified that blood from the group with low cluster activity was enriched for caffeine and a number of its metabolites, compared with blood from the group with high cluster activity. (Examples of these metabolites are theophylline, also found in tea, and theobromine, which abounds in chocolate.)
Incubating immune cells with caffeine and its breakdown products along with the inflammation-triggering nucleic acid metabolites substantially prevented the latter from exerting their powerful inflammatory effect on the cells.
What we've shown is a correlation between caffeine consumption and longevity.
"That something many people drink - and actually like to drink - might have a direct benefit came as a surprise to us," said Davis, who noted that the study did not prove a causal link. "We didn't give some of the mice coffee and the others decaf. What we've shown is a correlation between caffeine consumption and longevity. And we've shown more rigorously, in laboratory tests, a very plausible mechanism for why this might be so."
Other Stanford co-authors are postdoctoral scholars Junlei Chang, PhD, Christopher Bohlen, PhD, and Gabriela Fragiadakis, PhD; former graduate student Matthew Spitzer, PhD; life science research associate Edward Ganio; assistant professor of anesthesia, perioperative and pain medicine Brice Gaudilliere, MD, PhD; professor of microbiology and immunology Garry Nolan, PhD; and professor of hematology Calvin Kuo, MD, PhD.
Researchers from the Sidra Medical and Research Center in Qatar, the French National Institute of Health and Medical Research and the University of North Carolina also co-authored the study.
The study was funded by the National Institute of Allergy and Infectious Diseases (grant U19AI090019) and the Ellison Medical Foundation.
Stanford's Department of Microbiology and Immunology also supported the work.
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