Reference: EBioMedicine. 2022 Dec 13 early online
Practice Point: Consider a more narrow range of normal for serum sodium.
EBM Pearl: Do not leap from association to causation based only on observational data
Is “drink more water” one of your New Year’s Resolutions? A recent study published in the Lancet-sponsored eBioMedicine assessed the relationship of serum sodium, which is a marker of hydration, to premature aging, chronic disease, and mortality. Given evidence that chronic water restriction in mice leads to shorter lifespans, authors hypothesized that hydration has an integral effect on aging and that optimal hydration could potentially slow down the process.
Researchers analyzed data from the Atherosclerosis Risk in Communities study – an ongoing prospective cohort of more than 15,000 adults enrolled from 1985-1987 (aged 45-66 years at enrollment) and followed every three years for up to 25 years. The average fasting serum sodium from visits 1 and 2 was used as a proxy for hydration status in study participants. Speed of aging was assessed via a biological age (BA) calculation, the development of chronic disease, and all-cause mortality. BA was calculated with a formula integrating 15 age-related proxies for health such as: systolic blood pressure, forced expiratory volume, and serum markers of metabolism and inflammation. Participants with serum sodium levels outside the reference range (135-146 mmol/l), a blood glucose >140 mg/dL, a BMI >35 kg/m2, and the use of blood pressure or cholesterol-lowering medications were excluded from analysis.
After exclusions, data from 11,255 participants were analyzed. A serum sodium of 137-142 mmol/l was associated with the lowest mortality rate (26.2%), with increased mortality noted at both ends of the normal spectrum 135-136.5 mmol/l (39.3%) and 144.5-146 mmol/l (34.5%). A serum sodium >142 mmol was also associated with a 39% increased risk of chronic disease (hazard ratio [HR] = 1.39) and 10-15% increased odds to be biologically older than chronological age. This increased to 50% in participants with serum sodium levels >144 mmol/l. Notably, a higher biologic age was associated with an increased risk of chronic disease (HR = 1.70) and premature mortality (HR = 1.59).
Feeling thirsty yet? Well, although the evidence supports an association between an elevated sodium and accelerated aging, it also shows that low serum sodium may be a problem. The authors make a pretty big leap to assume that normal serum sodium can be used as a proxy for hydration status given volume status does not always correlate with serum sodium. It’s also unclear which way the association goes – is it higher or lower sodium which results in chronic disease or is it chronic disease which leads to changes in sodium? Excluding participants with abnormal sodium levels, diabetes, obesity, or taking medication for hypertension or hyperlipidemia was an attempt to control for confounders, however it greatly limits the generalizability of the results and does not exclude other confounders which might account for the increased risk seen with sodium at the edges of the normal range. This observational study certainly does not prove a causal link. Perhaps the results may facilitate a discussion regarding hydration practices with patients but otherwise its impact on clinical practice is slim. We’re not saying hydrating is not a good idea – it's just this study is not evidence for it! The real takeaway may be that the normal range of sodium may be too wide, although it is not clear what interventions this might suggest.
For more information, see the topic Dehydration and Hypovolemia in Adults in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Nicole Jensen, MD, Family Physician at WholeHealth Medical. Edited by Alan Ehrlich, MD, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; Katharine DeGeorge, MD, MS, Deputy Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia; Dan Randall, MD, Deputy Editor at DynaMed; Vincent Lemaitre, PhD, Senior Medical Writer at DynaMed; and Sarah Hill, MSc, Associate Editor at DynaMed.