Clonal hematopoiesis

Clonal hematopoiesis is what happens when a few blood-forming stem cells, some carrying mutations, come to make a large share of your blood. It is common with age, it is the one part of stem-cell aging you can read off a blood sample, and it raises the risk of blood cancer (though the absolute risk stays small) and heart disease. It is measurable, but not yet something you can act on.

Don't seek out testing as a healthy adult: no treatment aimed at it has been shown to help. If it turns up on a genetic test, the practical response is the usual one, which is not smoking and keeping cardiovascular risk factors in check.

What it is

Your blood is made by stem cells in the bone marrow. In adults under about 65 it is made evenly by a large, diverse pool of roughly 20,000 to 200,000 blood-forming stem cells, each of which picks up about 17 new DNA mutations a year from birth. After about 75 that diversity collapses: in each older person studied, 30 to 60% of all blood came from just 12 to 18 expanded clones. Most of those clones had started growing before age 40, and only about 1 in 5 carried a known cancer-driver mutation. That picture comes from whole-genome sequencing in just 10 people, so treat the exact figures as an illustration.^[1]

When an expanding clone carries a mutation in a growth-driver gene, most often the epigenetic regulators DNMT3A, TET2 or ASXL1, the condition is called clonal hematopoiesis of indeterminate potential (CHIP): a detectable mutant clone in someone with normal blood counts and no cancer.

How common it is

Standard sequencing finds CHIP in about one in ten people over 65, rising to nearly one in five in their 90s.^[2]^[3] How common it looks depends on how small a clone the test can detect: in a small study using ultra-sensitive sequencing, tiny clones turned up in 95% of the healthy 50- to 60-year-olds tested.^[4]

What it does to your risk

These figures come from large human cohorts and a pooled analysis of 88 studies, so they are well established, but they are associations.

Blood cancer. Carriers have about four times the risk of a later blood cancer when studies are pooled; the first two large studies put it at 11 to 13 times. The absolute risk stays small, about 0.5% to 1% a year, at the higher end with large clones.^[5]^[6]
Death from any cause. About a third higher in the pooled data.^[7]
Heart disease. Pooled across studies, people with CHIP have about 75% higher risk of coronary heart disease and about 40% more cardiovascular events overall; a higher risk of dying from heart disease shows up only in people with larger clones.^[8] In the original studies, carriers had about four times the risk of a heart attack at a young age after accounting for age, sex, diabetes and smoking. In mice, bone marrow lacking one of the commonly mutated genes produced larger artery plaques, which fits the idea that the mutant immune cells stoke inflammation in the artery wall.^[9] The American Heart Association now also links CHIP to heart failure, atrial fibrillation and blood clots.^[10]

The gene and the clone size matter. Clones carrying only a DNMT3A mutation, the most common kind, showed no clear extra risk of myeloid blood cancer or of death.^[11] The size of the cardiovascular risk also depends on which gene is mutated and how big the clone is.^[12]

One finding that cuts the other way

Several studies have linked CHIP, particularly larger clones, to a lower risk of Alzheimer's dementia (about a third lower odds in one analysis). In the brains of a handful of carriers studied after death, the same mutant blood-derived cells made up a large share of the brain's own immune cells (microglia), although what they do there is not yet known.^[13]^[14] The picture is not settled: in about 465,000 UK Biobank participants, CHIP showed no link to Alzheimer's and a modestly higher risk of brain disease linked to blood-vessel damage.^[15]

Measurable is not actionable

No treatment aimed at CHIP has been shown to prevent heart disease, and testing healthy people is not part of routine care. CHIP is increasingly found by chance during genetic testing, especially in cancer care, and specialists are still working out when deliberate testing helps, for example for persistent unexplained low blood counts or before cancer chemotherapy.^[16]^[17]

The only treatment hints are exploratory subgroup findings from heart trials of anti-inflammatory drugs. In heart-attack survivors with raised inflammation, those with TET2-mutant clones had about 60% fewer cardiovascular events on the antibody canakinumab, though not clearly more benefit than other patients got. In people with coronary disease, low-dose colchicine slowed the growth of TET2 clones but not of clones overall. Both need confirmation.^[18]^[19]

What may slow it

Smoking, obesity and chronic inflammation help these clones expand.^[20] Exercise may help in the other direction, though the evidence is observational. In a snapshot of about 91,000 adults who wore activity trackers, each extra hour a day of moderate-to-vigorous activity went with about 14% lower odds of carrying a clone driven by genes other than DNMT3A; DNMT3A clones showed no link.^[21] In a Chinese cohort of about 6,100 adults followed for 12 years, the extra heart-disease risk that comes with clonal hematopoiesis showed up in people with intermediate or poor lifestyles but was not detectable in those with a healthy lifestyle, though that estimate was imprecise.^[22]

Sleep is a mouse-only story so far: in mice carrying mutant clones, unbroken sleep slowed the clones' growth, but only for some mutations and not for DNMT3A. No study has shown that poor sleep causes clonal hematopoiesis in people.^[23]

This is the measurable face of stem-cell exhaustion, and a bridge to chronic inflammation.

What to do

Don't order a test to find out. Testing healthy people is not routine care, and no treatment aimed at CHIP has been shown to help.
If a test finds it, ask about clone size and the gene involved; both change what the result means.
Do the usual heart-protective things: don't smoke, keep weight, blood pressure and cholesterol in check, and stay active. Smoking and obesity are linked to faster clone growth, and active people are somewhat less likely to carry some clones.