Bipolar disorder ages the brain faster, and lithium is one of the few drugs that pushes back
STUDY: Rybakowski JK et al, Pharmaceuticals 2026
STUDY TYPE: Narrative review
FUNDING: Independent
Background
Bipolar disorder shortens life expectancy by ten to twenty years. Suicide and vascular disease are among the top causes of premature mortality, and faster biological aging likely contributes as well.
Patients with bipolar disorder tend to have shorter telomeres, more brain aging on imaging, and higher levels of the inflammatory proteins that are secreted by aging (“senescent”) cells. Cellular senescence, in which stressed cells stop dividing but keep pushing out inflammatory signals, has emerged as a mechanism linking mood disorders to neurodegeneration.
Lithium stands out among mood stabilizers in several ways:
- Broader neuroprotective effects
- Stronger protection against new mood episodes and preservation of functioning
- Anti-dementia properties
- Lower rates of suicide and medical mortality
This review looks at whether it acts as a senostatic agent, reducing the inflammatory output of aging, senescent cells. The lead author, Janusz Rybakowski, helped discover lithium’s anti-viral properties (more on that in our Carlat interview with him or the podcast version).
Across cell models, lithium reduced classic senescence markers, including SA-beta-gal activity and p16 and p21 expression, in astrocytes and neurons under oxidative stress, sometimes independent of glycogen synthase kinase-3 beta (GSK-3 beta), an enzyme targeted by lithium that regulates cell death.
As we age, the ends of our DNA (the telomeres) crumbles, a bit like the pages of an old book. Lithium prevents this telomeric aging, strengthening DNA repair and lowering oxidative stress in healthy volunteers on therapeutic doses. In patients with bipolar disorder, long-term lithium correlated with longer telomeres in leukocytes, and with higher telomerase (TERT) expression. The UK Biobank study, however, showed no such effect.
A separate cohort linked lithium to a lower brain-predicted age difference, a neuroimaging measure of how much older the brain looks than a patient’s actual age.
Lithium dampened the senescence-associated secretory phenotype, reducing inflammatory cytokines like IL-6, TNF-alpha, and IL-1beta and reducing microglial activation. The effect was not uniform. In endothelial cells, lithium induced a senescent-like state by upregulating MMP-1, a reminder that its effects depend on cell type.
The authors conclude lithium looks more like a senomorphic drug, one that mutes senescent cells’ damage, rather than a senolytic that clears them.
Real World Evidence
The mechanisms look promising, but does lithium actually extend life? It does in yeast, worms (C. elegans), fruitflies (drosophila), and preserves memory in rapidly aging mice.
In humans, lithium in the drinking water is associated with longer lifespans. Patients with bipolar disorder live longer on lithium compared to other mood stabilizers, a finding first observed with suicide rates but since extended to medical causes. We see lower rates of osteoporosis, cancer, vascular disease, and stroke with lithium, though most of this is correlation, not clear causation.
Practice Implications
- Word of lithium’s anti-aging properties is spreading, in part due to marketing of lithium orotate. The message destigmatizes the mineral, and is worth mentioning alongside discussion of its medical risks: renal, thyroid, parathyroid, rare arrhythmias, and toxicity.
- Don’t avoid lithium in the elderly. Rather, there is some evidence that it works better in this population, where inflammation and vascular disease are major contributions to depression. And a new studies highlight its medical safety in older adults and all adults.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
