EPIGENETIC CLOCK PREDICTS LIFE EXPECTANCY

UCLA-led study shows 5 percent of population ages faster, faces shorter lifespan

The rate of your biological clock influences how long you'll live.

Why do some people lead a perfectly healthy lifestyle yet still die young? A new international study suggests that the answer lies in our DNA.

Newswise, October 3, 2016 — UCLA geneticist Steve Horvath led a team of 65 scientists in seven countries to record age-related changes to human DNA, calculate biological age and estimate a person’s lifespan. A higher biological age—regardless of chronological age—consistently predicted an earlier death.

The findings are published in today’s edition of the journal Aging.

“Our research reveals valuable clues into what causes human aging, marking a first step toward developing targeted methods to slow the process,” said principal investigator Horvath, a professor of human genetics and biostatistics at UCLA’s David Geffen School of Medicine and Fielding School of Public Health.

Drawing on 13 sets of data, including the landmark Framingham Heart Study and Women’s Health Initiative, a consortium of 25 institutions analyzed the DNA in blood samples collected from more than 13,000 people in the United States and Europe.

Applying a variety of molecular methods, including an epigenetic clock developed by Horvath in 2013, the scientists measured the aging rates of each individual.

The clock calculates the aging of blood and other tissues by tracking methylation, a natural process that chemically alters DNA over time. By comparing chronological age to the blood’s biological age, the scientists used the clock to predict each person’s life expectancy.

“We were stunned to see that the epigenetic clock was able to predict the lifespans of Caucasians, Hispanics and African-Americans,” said first author Brian Chen, a postdoctoral fellow at the National Institute on Aging.

“This rang true even after adjusting for traditional risk factors like age, gender, smoking, body-mass index, disease history and blood cell counts.”

The group’s findings, however, don’t bode well for everyone.

“We discovered that 5 percent of the population ages at a faster biological rate, resulting in a shorter life expectancy,” Horvath said. “Accelerated aging increases these adults’ risk of death by 50 percent at any age.”

For example, two 60-year-old men, Peter and Joe, both smoke to deal with high stress. Peter’s epigenetic aging rate ranks in the top 5 percent, while Joe’s aging rate is average. The likelihood of Peter dying within the next 10 years is 75 percent compared to 60 percent for Joe.

The preliminary finding may explain why some individuals die young – even when they follow a nutritious diet, exercise regularly, drink in moderation and don’t smoke. 

“While a healthful lifestyle may help extend life expectancy, our innate aging process prevents us from cheating death forever,” Horvath emphasized. “Yet risk factors like smoking, diabetes and high blood pressure still predict mortality more strongly than one’s epigenetic aging rate.”

Scientists have long searched to identify biomarkers for biological age, according to coauthor Dr. Douglas Kiel, a professor at Harvard Medical School and a senior scientist for the Institute of Aging Research at Hebrew SeniorLife.

“In geriatric medicine, we are always struck by the difference between our patients’ chronological age and how old they appear physiologically,” said Kiel.

“This study validates the use of DNA methylation as a biomarker for biological age. And if we can prove that DNA methylation accelerates aging, we can devise strategies to slow the rate and maximize a person’s years of good health.”

The precise role of epigenetic changes in aging and death, however, remains unknown, said coauthor Dr. Themistocles Assimes, an assistant professor of cardiovascular medicine at Stanford University School of Medicine.

“Do the epigenetic changes associated with chronological aging directly cause death in older people?” said Assimes.

“Perhaps they merely enhance the development of certain diseases--or cripple one’s ability to resist the progression of disease after it has taken root. Future research is needed to address these questions.”

Larger studies focused only on cases with well-documented causes of death will help scientists tease out the relationship between epigenetic age and specific diseases, he added.

By 2017, according to the World Health Organization, the number of people worldwide over age 65 will outnumber those under age 5 for the first time in recorded history.

By 2050, the proportion of the global population over 60 will double from 11 to 22 percent. Many countries will be ill-prepared to keep pace with the high costs associated with disease and disability as more people live longer, said Horvath.

“We must find interventions that prolong healthy living by five to 20 years. We don’t have time, however, to follow a person for decades to test whether a new drug works.” said Horvath. “The epigenetic clock would allow scientists to quickly evaluate the effect of anti-aging therapies in only three years.”

The University of California has applied for a provisional patent on the epigenetic clock.

Natural Metabolite Might Reset Aging Biological Clocks

Newswise, October 16, 2015 — As we age, our biological clocks tend to wind down – but why? A Weizmann Institute of Science research team has now revealed an intriguing new link between a group of metabolites whose levels drop as our cells age and the functioning of our circadian clocks – mechanisms encoded in our genes that keep time to cycles of day and night. 

Their results, which appeared in Cell Metabolism, suggest that the substance, which is found in many foods, could help keep our internal timekeepers up to speed.

Dr. Gad Asher’s lab in the Department of Biological Chemistry investigates these circadian clocks, trying to understand how these natural timekeepers help regulate, and are affected by, everything from nutrition to metabolism. 

In the present study, he and his research student Ziv Zwighaft were following clues that certain metabolites called polyamines could be tied to the functioning of circadian clocks. 

We get polyamines from food, but our cells manufacture them as well. These substances are known to regulate a number of essential processes in the cell, including growth and proliferation. And the levels of polyamines have been found to naturally drop as we age.

Working with mice and cultured cells, they found that, indeed, enzymes that are needed to manufacture polyamines undergo cycles that are tied to both feeding and circadian rhythms of day and night. In mice engineered to lack a functional circadian clock, these fluctuations did not occur.

As the researchers continued to investigate, they discovered a sort of feedback loop: polyamine production is not only regulated by circadian clocks but, in turn, also regulate the ticking of those clocks. In cell cultures, adding high levels of polyamines more or less obliterated the circadian rhythm, while maintaining low levels slowed the clock by around two hours. 

“The polyamines are actually an embedded part of the circadian clockwork,” says Dr. Asher.

The scientists then asked how this plays out in younger and older mice, with their naturally higher or lower polyamine levels. It is known that the circadian clocks of elderly mice run more slowly; concomitantly, their polyamine levels decline. 

The team found they could slow down the clocks in the young mice by administering a drug to inhibit polyamine synthesis. In contrast, adding a polyamine to the drinking water of the older mice made their clocks run faster than others of their age group and actually restored their function, similar to that of the young mice.

Dr. Asher and his team intend to continue investigating the function of polyamines in circadian systems. 

“This discovery demonstrates the tight intertwining between circadian clocks and metabolism,” says Mr. Zwighaft. “Our findings today rely on experiments with mice, but we think they might hold true in humans. If so, they will have broad clinical implications,” Dr. Asher says. 

“The ability to repair the clock simply, through nutritional intervention with polyamine supplementation, is exciting and obviously of great clinical potential.”

Dr. Gad Asher’s research is supported by the Willner Family Leadership Institute; the Yeda-Sela Center for Basic Research; the Adelis Foundation; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Crown Endowment Fund for Immunology Research; and the Samuel M. Soref and Helene K. Soref Foundation.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. The Institute’s 3,800-strong scientific community engages in research addressing crucial problems in medicine and health, energy, technology, agriculture, and the environment. 

Outstanding young scientists from around the world pursue advanced degrees at the Weizmann Institute’s Feinberg Graduate School. The discoveries and theories of Weizmann Institute scientists have had a major impact on the wider scientific community, as well as on the quality of life of millions of people worldwide