Biological age

Blood “aging clocks” were linked to reaching 90, but not to reaching it with a sharp mind

In 5,844 older American women, all 15 epigenetic clocks measured in the late 1990s were linked to the chance of living to 90, the newer clocks most strongly. But none of them told apart the women who reached 90 with their thinking intact from those who reached 90 with memory problems or dementia. It is an observational study.

Living to 90 is no longer rare in the United States. According to the paper, an American woman who has reached 65 has about a 35% chance of seeing her 90th birthday. But people arrive at that age in very different shape: some still think clearly, others live with memory loss or dementia. A blood test that could tell, decades ahead, who is likely to reach old age with a working mind would be a powerful research tool.

One candidate is the epigenetic clock. Along our DNA sit small chemical tags called methyl groups, which help switch genes on and off. Their pattern shifts with age, so a formula reading those tags can estimate a person's "biological age". If the clock runs ahead of someone's actual age, that is called age acceleration. Faster clocks have been linked to earlier death in many studies, but no clock had been built to predict survival to a very old age, let alone survival with preserved thinking.

What they did

The team used the Women's Health Initiative Memory Study, which began in 1996–1999 with women aged 65 to 79 who had no memory or thinking problems at the time. It was set up alongside large US trials of hormone therapy, and it kept checking the women's memory and thinking every year, from 2008 by telephone, through 2021.

  • Who: 5,844 women whose birth years meant they could have turned 90 by February 2024.
  • The clocks: DNA from blood drawn at the start was analysed for 15 widely used clocks. These range from "first-generation" clocks, built to match a person's calendar age, to newer ones such as GrimAge2 and DunedinPACE, built to track health and the pace of aging. Three clocks run the other way: higher values mean slower aging.
  • The outcomes: reaching 90 versus dying before 90, and then a three-way split: reaching 90 with thinking intact, reaching 90 with mild cognitive impairment (memory or thinking problems short of dementia) or probable dementia, or dying earlier.
  • Fair comparison: the analysis accounted for age, race and ethnicity, education, smoking, physical activity, body weight, diabetes, heart disease, cancer, which hormone therapy group a woman was in, and the mix of white blood cells in the sample, since different blood cells carry different tag patterns.

What they found

Of the 5,844 women, 3,233 (55.3%) reached 90: 1,726 with thinking intact, 956 with cognitive impairment, and the rest could not be classified. Another 2,611 died before 90.

  • Every clock was linked to reaching 90. For the first-generation clocks, each step of one standard deviation (a typical spread between people) towards faster aging went with 7% to 18% lower odds of reaching 90.
  • Newer clocks did better. The strongest links were for GrimAge2 (an odds ratio of 0.66, roughly a third lower odds per step), a refined version of GrimAge (0.64), a refined PhenoAge (0.73) and DunedinPACE (0.77). A clock estimating the length of telomeres, the caps that guard the ends of chromosomes, pointed the other way as expected (1.35).
  • No clock separated the two kinds of 90-year-olds. The odds ratios for reaching 90 with and without cognitive impairment were similar, with overlapping ranges, and the small differences often leaned towards weaker links with healthy thinking.
  • Even the one clock built partly on a thinking test (the Intrinsic Capacity clock) gave 1.16 for reaching 90 with preserved thinking and 1.19 for reaching it without.
  • Among the women who reached 90, the clocks were generally not linked to who later developed cognitive impairment.

What to keep in mind

  • Women only. The authors note the results need to be repeated in men.
  • Some missing classifications. The researchers could not tell the cognitive status at 90 of 9.3% of the women, although they report that the clock results looked very similar either way. For women without a recent study assessment, cognitive status was taken from questionnaires that asked about memory problems or a doctor's dementia diagnosis.
  • Not a contest. The study was not designed to prove that one clock is better than another; the authors call comparisons between clocks exploratory.
  • Links, not causes. This is an observational study. In the authors' words, it is "not possible to infer causality" from it; a fast clock went together with dying earlier, but the study cannot say the aging the clock measures is the cause.
  • One snapshot. The clocks were measured once, from a single blood sample taken around age 65 to 79.

Why it matters

Epigenetic clocks are increasingly used as a stand-in for aging in research, including trials of treatments meant to slow it. This study confirms, in a long follow-up of thousands of women, that the clocks track how long people live, and GrimAge2 looked especially promising. But living long and living long with a clear mind are not the same thing, and on the second question the current clocks were silent. The authors suggest one reason: some women who reach 90 with dementia may age slowly in body yet differ in how their brains age, something today's clocks don't capture. Their conclusion is that new clocks are needed that can tell long survival with intact thinking from long survival without it.

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