Immune aging Preprint

Mutated blood stem cells were linked to frailty in about 730,000 people

In four large groups of adults, people carrying a growing family of mutated blood cells, which becomes common with age, became frail somewhat more often and somewhat sooner. Mice with one such mutation in their blood also declined faster. The human part shows a link, not proof of cause, and the study is not yet peer-reviewed.

Some people stay sturdy into old age while others become frail, with less reserve in many body systems at once. Frailty raises the risk of disability, hospital stays and death, but what sets it off in one person and not another is still poorly understood. A new preprint, not yet peer-reviewed, looks at one candidate in the blood.

Every day, blood stem cells in the bone marrow divide to make new blood cells. Over a lifetime they pick up random mutations. Now and then a mutation gives one stem cell an edge, so its descendants slowly take over a noticeable share of the blood. This is called clonal hematopoiesis ("a clone of blood-forming cells"). When the mutation sits in one of the genes known from blood cancers, it is called CHIP, clonal hematopoiesis of indeterminate potential. It is found in more than one in ten adults over 60 and has already been tied to heart disease and other age-related conditions. Another form involves larger changes, where a piece of a chromosome is lost or duplicated in the clone (mosaic chromosomal alterations).

What they did

The team pooled three biobanks that combine DNA sequencing with medical records: UK Biobank, the US All of Us programme and BioVU, the biobank of Vanderbilt University Medical Center. After excluding people with blood cancers and keeping ages 40 to 70, that left 726,091 people.

  • Frailty was measured with the Hospital Frailty Risk Score, which adds up weighted diagnosis codes linked to frailty in each person's records. Crossing a set threshold counted as becoming frail; a higher one, as severe frailty.
  • Fair comparison: the analysis took age, sex, smoking and genetic ancestry into account.
  • Other measures: in UK Biobank, a 49-item questionnaire index and a blood-protein score that predicts staying free of major diseases. In 3,997 women of the Women's Health Initiative, frailty was measured directly (walking speed, grip strength and more). In 205 adults aged 65 or older, clinicians had rated frailty on a standard scale.
  • Mice: mice whose blood cells lacked a working Tet2 gene, one of the common CHIP genes, were compared with normal littermates.
  • Proteins: in UK Biobank, they checked 148 blood proteins tied to T cell activation.

What they found

  • More frailty with CHIP. After ten years, about 31.8% of CHIP carriers had become frail, against 24.0% of non-carriers. After the adjustments, CHIP was linked to a 12% higher risk of frailty and a 19% higher risk of severe frailty.
  • Depends on the gene. The most common CHIP gene, DNMT3A, showed only a small link (5%). TET2 (19%) and ASXL1 (27%) showed larger ones. JAK2 had the biggest estimate for severe frailty (about twice the risk), but only 69 carriers.
  • Chromosome changes on the ordinary chromosomes were linked to a 13% higher risk; loss of the X or Y chromosome in blood cells was not, after adjustment.
  • Faster progression. Carriers' frailty scores rose a little faster.
  • Other measures pointed the same way, with some caveats: the questionnaire index and the protein score were worse in CHIP carriers. In the Women's Health Initiative the link was in the same direction but not statistically significant overall; it was significant only for larger clones. In the 205 older adults, CHIP carriers had about twice the odds of a higher frailty rating.
  • Mice. Young adult Tet2 mice moved around less. In middle age they had a weaker grip, did worse in a hanging test and scored worse on a mouse frailty index. Their T cells had shifted away from "naïve" cells, which respond to new germs, towards memory cells, a pattern seen in immune aging.
  • Immune proteins. Of the 148 T-cell proteins, 100 were linked to later frailty. Statistically, individual proteins accounted for roughly 4% to 18% of the CHIP–frailty link each; for TET2 one protein, BAFF, accounted for about 59%.

What to keep in mind

  • Links, not causes, in people. The authors state that the human analyses are observational and can't prove cause; other health problems and differences in how often people see doctors may still play a part. The title's claim that clonal hematopoiesis "accelerates" frailty is the authors' interpretation, resting partly on the mice.
  • A score built from diagnosis codes. The main frailty measure came from medical records, so it depends on how diagnoses were coded and recorded, which differs between health systems.
  • One snapshot of the clone. The mutations were mostly measured once, so the study can't follow how clones grew.
  • Limited subgroups. The protein data covered only UK Biobank participants who had them. In the women's study, few new cases, dropouts and a gap of about 15 years may have weakened the results.
  • Modest effects. A 12% higher risk is small for any one person, and nearly all UK Biobank participants were of European ancestry.
  • One mouse model. The mice lacked Tet2 in all their blood cells, which is not the same as a small clone in an older person.

Why it matters

Clonal hematopoiesis has so far been studied mostly one disease at a time. This study suggests it may also be linked to the general loss of reserve that makes up frailty, and that the type of mutation matters. The mouse and protein results point to T cells as one possible route. Whether checking for these mutations could help predict frailty, or whether anything aimed at the immune system could slow it, are questions the authors leave for future long-term and intervention studies.

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