When several of the body's chemical systems drift off balance at once, risks seem to add up

A healthy body keeps its chemistry within narrow limits: blood sugar, fats, salts and hundreds of other small molecules are held steady, and after a stress (an infection, a hard workout) they return to their usual levels. Biologists call this steady state homeostasis. With age this control loosens. Researchers call the result biological dysregulation: a person's chemistry drifts away from the pattern seen in healthy people, and the drift has been linked to disease and death before.

A Canadian study now asks whether this drift is one thing or several, and whether it matters if more than one part of the body's chemistry is off at the same time.

What they did

The team used the Canadian Longitudinal Study on Aging, which follows tens of thousands of adults aged 45 and older. In 9,992 participants, a blood sample taken at the start had been analysed for 811 metabolites, the small molecules that cells make and use, such as sugars, fats and amino acids.

As a yardstick they took a "healthy reference" group: participants aged 45 to 54 who were not frail. For everyone else, a statistical measure scored how far their whole metabolite profile lay from that reference. A bigger distance meant more dysregulation. The researchers then grouped metabolites that tend to rise and fall together into separate "systems", scored the drift within each system, and compared the scores with people's health, their epigenetic age (a biological age read from DNA methylation), new diseases over six years and deaths over up to nine years. They repeated the main analyses in the UK Biobank, using a smaller metabolite panel and a large set of blood proteins.

What they found

• Drift grows with age. Dysregulation was higher, and more variable, in older age groups. About 21% of the differences between people could be traced to their genes.
• It tracks known risk factors. Scores were higher in people with low incomes, who sat most of the day, who smoked heavily, who were underweight or severely obese, frail, or very distressed. They also rose with three of four epigenetic clocks tested.
• It is linked to death. Each step of one standard deviation (a measure of spread) in the overall score was linked to a 59% higher risk of dying during follow-up in men and 49% in women, even after taking epigenetic age or frailty into account.
• The drift has separate parts. The metabolites fell into five systems plus a group of leftovers that fit nowhere. The systems' scores were only weakly linked to each other, and they related to different problems: one, rich in fat-processing molecules, was the only one linked to new cases of dementia (41 cases); another, tied to frailty and inflammation, was linked to several new diseases, most strongly kidney disease.
• Several systems off at once looked worse than one big score. Compared with people who were high in no system, those high in three systems had about twice the risk of death, and those high in four or more about three times (hazard ratios 2.17 and 3.27). Being in the top third of the overall score, compared with the bottom third, carried a smaller increase (1.87). For kidney disease the gap was larger still: about fivefold for four or more systems.
• The idea carried over. In the UK Biobank, drift scores built from metabolites or from proteins also rose with age and were linked to death and to most of the diseases studied.

What to keep in mind

• Not yet peer-reviewed. This is a preprint.
• Associations only. The study is observational: it shows which people had higher risks, not that the drift causes disease, and not that lowering a score would help.
• Blood only. The authors note that blood metabolites may not reflect what happens inside tissues.
• Mostly white participants, aged 45 and over. The authors say the findings need checking in other ethnic groups, and may not apply to younger people.
• Many unknown molecules. Nearly half of the metabolites have no known identity, which makes it hard to say what each system does.
• Small numbers for some diseases. The dementia result rests on 41 new cases, and diseases were reported by the participants themselves.
• A one-time sample. Blood chemistry was measured once at the start.

Why it matters

Many "biological age" scores boil the body down to a single number. This study suggests that the way aging bodies lose their chemical balance has several separate parts, and that trouble in several parts at once may matter more than the overall total. The authors argue that this could make risk predictions more precise and that approaches aimed at several systems might work better than ones aimed at a single system. That is a hypothesis for future trials; this study did not test any treatment.