Investigators at the Stanford University School of Medicine and the Buck
Institute for Research on Aging have built an inflammatory-aging clock
that’s more accurate than the number of candles on your birthday cake in
predicting how strong your immune system is, how soon you’ll become frail or
whether you have unseen cardiovascular problems that could become clinical
headaches a few years down the road.
In the process, the scientists fingered a bloodborne substance whose
abundance may accelerate cardiovascular aging.
The story of the clock’s creation was published today (July 12, 2021) in
Nature Aging.
“Every year, the calendar tells us we’re a year older,” said David Furman,
PhD, the study’s senior author. “But not all humans age biologically at the
same rate. You see this in the clinic — some older people are extremely
disease-prone, while others are the picture of health.”
This divergence, Furman said, traces in large part to differing rates at
which people’s immune systems decline. The immune system — a carefully
coordinated collection of cells, substances, and strategies with which
evolution has equipped us to deal with threats such as injuries or invasions
by microbial pathogens — excels at mounting a quick, intense, localized,
short-term, resist-and-repair response called acute inflammation. This “good
inflammation” typically does its job, then wanes within days. (An example is
that red, swollen finger you see when you have a splinter, and the rapid
healing that follows.)
As we grow older, a low-grade, constant, bodywide “bad inflammation” begins
to kick in. This systemic and chronic inflammation causes organ damage and
promotes vulnerability to a who’s who of diseases spanning virtually every
organ system in the body and including cancer, heart attacks, strokes,
neurodegeneration and autoimmunity.
To date, there have been no metrics for accurately assessing individuals’
inflammatory status in a way that could predict these clinical problems and
point to ways of addressing them or staving them off, Furman said. But now,
he said, the study has produced a single-number quantitative measure that
appears to do just that.
Furman directs the Stanford 1000 Immunomes Project and is a visiting scholar
at Stanford’s Institute for Immunity, Transplantation and Infection. In
addition, he’s an associate professor at the Novato, California-based Buck
Institute for Research on Aging and director of the Artificial Intelligence
Platform at the same institute.
Lead authors of the study are Nazish Sayed, MD, PhD, assistant professor of
vascular surgery at Stanford, and Yingxiang Huang, PhD, senior data
scientist at the Buck Institute.
1,001 blood samples
For the 1000 Immunomes Project, blood samples were drawn from 1,001 healthy
people ages 8-96 between 2009 and 2016. The samples were subjected to a
barrage of analytical procedures determining levels of immune-signaling
proteins called cytokines, the activation status of numerous immune-cell
types in responses to various stimuli, and the overall activity levels of
thousands of genes in each of those cells.
The new study employed artificial intelligence to boil all this data down to
a composite the researchers refer to as an inflammatory clock. The strongest
predictors of inflammatory age, they found, were a set of about 50
immune-signaling proteins called cytokines. Levels of those, massaged by a
complex algorithm, were sufficient to generate a single-number inflammatory
score that tracked well with a person’s immunological response and the
likelihood of incurring any of a variety of aging-related diseases.
In 2017, the scientists assessed nearly 30 1000 Immunomes Project
participants ages 65 or older whose blood had been drawn in 2010. They
measured the participants’ speed at getting up from a chair and walking a
fixed distance and, through a questionnaire, their ability to live
independently (“Can you walk by yourself?” “Do you need help getting
dressed?”). Inflammatory age proved superior to chronological age in
predicting frailty seven years later.
Next, Furman and his colleagues obtained blood samples from an ongoing study
of exceptionally long-lived people in Bologna, Italy, and compared the
inflammatory ages of 29 such people (all but one a centenarian) with those
of 18 50- to 79-year-olds. The older people had inflammatory ages averaging
40 years less than their calendar age. One, a 105-year-old man, had an
inflammatory age of 25, Furman said.
To further assess inflammatory age’s effect on mortality, Furman’s team
turned to the Framingham Study, which has been tracking health outcomes in
thousands of individuals since 1948. The Framingham study lacked sufficient
data on bloodborne-protein levels, but the genes whose activity levels
largely dictate the production of the inflammatory clock’s cytokines are
well known. The researchers measured those cytokine-encoding genes’ activity
levels in Framingham subjects’ cells. This proxy for cytokine levels
significantly correlated with all-cause mortality among the Framingham
participants.
A key substance
The scientists observed that blood levels of one substance, CXCL9,
contributed more powerfully than any other clock component to the
inflammatory-age score. They found that levels of CXCL9, a cytokine secreted
by certain immune cells to attract other immune cells to a site of an
infection, begin to rise precipitously after age 60, on average.
Among a new cohort of 97 25- to 90-year-old individuals selected from the
1000 Immunomes Project for their apparently excellent health, with no signs
of any disease, the investigators looked for subtle signs of cardiovascular
deterioration. Using a sensitive test of arterial stiffness, which conveys
heightened risk for strokes, heart attacks and kidney failure, they tied
high inflammatory-age scores — and high CXCL9 levels — to unexpected
arterial stiffness and another portent of untoward cardiac consequences:
excessive thickness of the wall of the heart’s main pumping station, the
left ventricle.
CXCL9 has been implicated in cardiovascular disease. A series of experiments
in laboratory dishware showed that CXCL9 is secreted not only by immune
cells but by endothelial cells — the main components of blood-vessel walls.
The researchers showed that advanced age both correlates with a significant
increase in endothelial cells’ CXCL9 levels and diminishes endothelial
cells’ ability to form microvascular networks, to dilate, and to contract.
But in laboratory experiments conducted on tissue from mice and on human
cells, reducing CXCL9 levels restored youthful endothelial-cell function,
suggesting that CXCL9 directly contributes to those cells’ dysfunction and
that inhibiting it could prove effective in reducing susceptible
individuals’ risk of cardiovascular disease.
“Our inflammatory aging clock’s ability to detect subclinical accelerated
cardiovascular aging hints at its potential clinical impact,” Furman said.
“All disorders are treated best when they’re treated early.”
Reference:
Sayed, N., Huang, Y., Nguyen, K. et al. An inflammatory aging clock (iAge)
based on deep learning tracks multimorbidity, immunosenescence, frailty and
cardiovascular aging. Nat Aging (2021).
https://doi.org/10.1038/s43587-021-00082-y