Fox Chase team finds turning on tumor suppressor in immature mice triggers premature aging.[]

An international research team headed by scientists at the University of Edinburgh has identified genes linked to aging that could help to explain why some people age at different rates to others. Their newly reported study, which analyzed genetic data from more than a million people, suggests that maintaining healthy levels of iron in the blood might be key to aging better and living longer. The findings could feasibly help scientists design and develop drugs to reduce age-related diseases, extend healthy years of life, and increase the chances of living to old age free of disease.

“We are very excited by these findings as they strongly suggest that high levels of iron in the blood reduces our healthy years of life, and keeping these levels in check could prevent age-related damage,” commented research lead Paul Timmers, PhD, from the Usher Institute at the University of Edinburgh. “We speculate that our findings on iron metabolism might also start to explain why very high levels of iron-rich red meat in the diet has been linked to age-related conditions such as heart disease.”

Timmers and colleagues reported their findings in Nature Communications, in a paper titled, “Multivariate genomic scan implicates novel loci and haem metabolism in human ageing.”

Human aging is characterized by a progressive decline in the body’s ability to maintain homeostasis, which is linked with major causes of death, including heart disease, cancer, and dementia. However the timecourse of biological aging varies between people, the authors noted. Some people will develop chronic disease and die at a relatively young age, while others may live to a ripe old age, and be free from disease until the last few years.

How long we live is dependent on a variety of factors, the team continued. “A long and healthy life is determined by many different factors, including lifestyle, environment, genetics, and pure chance.” In fact, recent estimates suggest that the genetic components of both human lifespan and healthspan may only be about 10%, which makes genetic studies of these traits particularly challenging, as “noise” tends to obscure any true effects unless sample sizes are large. Nevertheless, the investigators noted, “… with sufficiently large samples, genome-wide association studies (GWAS) of aging traits have the potential to identify genes and pathways involved in the human aging process.”

For their study, the researchers pooled information from three public European-ancestry GWAS datasets to enable an analysis in unprecedented detail. Anonymized datasets linking genetic variation to healthspan, lifespan, and longevity were downloaded from the publicly available Zenodo, Edinburgh DataShare, and Longevity Genomics servers. The combined dataset was equivalent to studying 1.75 million lifespans or more than 60,000 extremely long-lived people. They evaluated the overlapping traits of healthspan, parental lifespan, and longevity.

The results indicated that the three traits were linked by genes. “Genetic correlations between publicly available healthspan, parental lifespan, and longevity GWAS reveal these traits share 50% or more of their underlying genetics,” the scientists commented. Their analyses identified 24 genomic regions that appeared to influence one or more of the three traits, and ten genomic regions that were linked to all three. “Ten regions are of particular interest as they associate with all three aging traits and are as such likely candidates to capture intrinsic aging processes, rather than extrinsic sources of aging.”

Further evaluation of the data showed that that gene sets linked to iron were overrepresented in the analysis of all three measures of aging. The researchers confirmed this using a statistical method known as Mendelian randomization (MR), which suggested that genes involved in metabolizing iron in the blood are partly responsible for a healthy long life. “ … in line with the highlighted pathways, we find a causal role for iron levels in healthy life in an MR framework,” they wrote. And while the team acknowledged that their study had a number of limitations, they concluded that “…the strong signal for heme metabolism, in combination with the MR results, suggests the evidence for the involvement of this pathway in human aging is reasonably robust.”

Blood iron is affected by diet, and abnormally high or low iron levels are linked with age-related conditions such as Parkinson’s disease, liver disease, and a reduction in the body’s ability to fight infection in older age. “Heme synthesis declines with age and its deficiency leads to iron accumulation, oxidative stress, and mitochondrial dysfunction,” they further noted. “In turn, iron accumulation helps pathogens to sustain an infection, which is in line with the known increase in infection susceptibility with age. In the brain, abnormal iron homeostasis is commonly seen in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease and multiple sclerosis.” Observational and other studies have also linked iron accumulation with early death, and with liver disease, osteoarthritis, and systemic inflammation.

The researchers cautioned that while much more work will be needed, it is feasible that future development of a drug that can mimic the influence of genetic variation on iron metabolism could help overcome some of the effects of aging. “This study, and follow-up work on the genes we have highlighted, will eventually lead to therapeutic targets that can reduce the burden of age-related diseases, extend the healthy years of life, and increase the chances of becoming long lived without long periods of morbidity,” they concluded.

Co-author Joris Deelen, PhD, research group leader at the Max Planck Institute for Biology of Ageing in Germany, further commented, “Our ultimate aim is to discover how aging is regulated and find ways to increase health during aging. The ten regions of the genome we have discovered that are linked to lifespan, healthspan, and longevity are all exciting candidates for further studies.”

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