Aging Rewires Neck Vessels and Brain Lipids in Female Mice Before Disease Strikes

Aging quietly transforms the highway that carries blood to the brain, and a new study suggests the damage begins far earlier—and in more intimate biochemical detail—than scientists previously appreciated. In research published in Physiological Reports, a team at the University of Tennessee traced how growing older reshapes both the function and the molecular makeup of the neck vasculature in healthy female mice, and how those vascular changes are mirrored by striking shifts in the chemical composition of the brain itself. The findings, gathered entirely from disease-free animals, offer a baseline map of normal neurovascular aging in females, a population in which cardiovascular and neurological diseases surge after menopause.

The research tackled a long-standing puzzle in vascular biology: why women fare disproportionately badly as they age. Although both sexes experience arterial stiffening and neurological decline with age, women show a higher incidence of cardiovascular disease and many neurological conditions after menopause compared with age-matched men. The link between arterial stiffness and mortality is nearly twice as strong in women as in men, and cognitive decline progresses more steeply in elderly females than in elderly males. Because aging-related vascular stiffening can alter the blood–brain barrier and brain function, the investigators reasoned that the earliest changes in the vessels of the neck—the carotid arteries and jugular veins—might be tightly coupled to biochemical remodeling inside the brain.

To capture that coupling, the team combined three complementary technologies in a single cohort of healthy female C57BL/6 mice. Ultrasound imaging, performed with a high-frequency transducer on a Vevo 3100 system, allowed them to measure vessel diameters and blood velocities in living animals, from which they calculated wall shear stress, circumferential cyclic strain, pulsatility index, and volumetric flow in the carotid artery. Histology then quantified the balance of elastin and collagen—the two structural proteins that determine whether an artery snaps back like a rubber band or behaves like a rigid pipe. Finally, two mass spectrometry approaches, liquid chromatography mass spectrometry and matrix-assisted laser desorption ionization mass spectrometry imaging, charted the lipid landscape of the carotid artery, jugular vein, and brain, mapping exactly where age-sensitive lipids reside in tissue.

The ultrasound results were unambiguous. Middle-aged females, at 52 weeks of age, showed a roughly 23.5 percent drop in average carotid velocity during systole compared with 12-week-old young females, and a 27.8 percent reduction in wall shear stress during systole, a difference that was highly statistically significant. Average volumetric flow, normalized to body weight, plummeted by about 55.2 percent with age. Because the reduction in shear stress was driven primarily by the decline in systolic velocity, the authors attribute it to age-related changes in vascular compliance and cardiac output. Circumferential cyclic strain and pulsatility index trended downward but did not reach statistical significance, while the jugular vein diameter grew about 11.6 percent larger in the older animals—evidence that even veins remodel with age.

Under the microscope, the structural counterpart of those functional losses came into focus. The elastin-to-collagen ratio in the carotid artery fell in middle-aged mice relative to young controls, a shift that reflects the fundamental biomechanics of aging arteries. Elastin fibers, which allow vessels to stretch and recoil, replenish at an extremely low rate throughout life; as they dwindle, stiffer collagen fibers accumulate in relative terms. A lower elastin-to-collagen ratio means diminished arterial compliance, limiting the vessel’s ability to dampen the pulsatile pressure generated by each heartbeat. When large arteries lose that damping capacity, the delicate microvasculature surrounding the brain is exposed to higher pulsatile energies than it can safely withstand, a mechanism that previous work has linked to damage of small vessels and the blood–brain barrier. Notably, the jugular vein showed the opposite trend, with a modest increase in its elastin-to-collagen ratio, suggesting that arteries and veins age along distinct structural trajectories.

The lipidomic data added a molecular dimension to this picture. In the brain, ten lipid headgroups—including hexosylceramides, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylinositol, phosphatidylserine, and sulfated hexosylceramides—decreased significantly with age, while N-acylethanolamines increased, possibly as a compensatory response to age-related stress or inflammation given their known neuroprotective roles. These reductions matter because the brain is among the most lipid-rich organs in the body. Phospholipids protect cells from damage, sphingolipids stabilize the myelin that insulates nerves, and low levels of these molecules can signal neuronal vulnerability. In the carotid artery, cardiolipins and lysophosphatidylethanolamines rose with age, changes the authors link to mitochondrial dysfunction and membrane remodeling within the vessel wall. A triglyceride species, TG 45:9, accumulated in the aged carotid—consistent with epidemiological evidence that triglycerides are the blood lipid most strongly associated with arterial stiffness—while the signaling lipid DG 55:10 declined, hinting at impaired endothelial responsiveness.

Perhaps the study’s most consequential technical insight came from comparing whole-brain and region-specific analyses. When the researchers ran an unsupervised principal component analysis on mass spectrometry imaging data from the entire brain, young and middle-aged animals overlapped almost completely, with only a faint suggestion of age-related variation. But when the same analysis was restricted to the hippocampus—the memory center known to be exquisitely sensitive to metabolic and mitochondrial stress—the two age groups separated cleanly, with minimal overlap. The dominant contributor to that separation was a cardiolipin-associated ion at mass-to-charge ratio 1489.73, which diminished in the middle-aged hippocampus. Cardiolipins are essential components of mitochondrial membranes, and their loss fits established models of mitochondrial dysfunction in brain aging. The lesson is methodological as much as biological: bulk analysis of the whole brain masks regional lipid remodeling that may drive cognitive decline, and imaging-based approaches can expose changes that homogenized tissue cannot.

Tying everything together, Pearson correlation analysis revealed moderate to strong associations—correlation coefficients exceeding 0.6 in magnitude—between vascular biomechanical measures such as wall shear stress and circumferential cyclic strain and specific lipid classes across tissues, including glycerolipids, phospholipids, and sphingolipids. The authors are careful to stress that these correlations do not establish causality, and because neuronal and glial endpoints were not directly measured, any link between vascular changes and downstream neurological consequences remains speculative. They also acknowledge limitations: the effect sizes were relatively small, the 52-week-old mice represent a middle-aged rather than truly aged cohort, and even careful use of anatomical landmarks could not eliminate all positional variability in imaging and biochemical sampling. More advanced aging or emerging pathology may be required to produce larger, more disruptive shifts in vascular metrics.

Even with those caveats, the study delivers a compelling integrated portrait of neurovascular aging in females. Declining blood flow, falling wall shear stress, stiffening arterial walls, and wholesale lipid remodeling in both vessel and brain appear together in otherwise healthy animals, well before overt disease. That timing matters: if neck vascular dysfunction genuinely precedes brain biochemical alteration, as related work from the same group suggests, the vasculature may offer an early warning system—and a potential intervention target—for the cognitive diseases that disproportionately afflict aging women. By establishing this baseline in disease-free mice, the team has laid groundwork for future mechanistic studies in models of neurodegeneration, and has underscored a point increasingly hard to ignore: brain aging cannot be understood without also understanding the blood vessels that feed it.

Subject of Research: The effects of aging on neck vascular function, vascular and brain lipid composition, and brain biochemistry in female mice.

Article Title: Impact of aging on neck vasculature and brain biochemistry in female mice

Article References: Jones, A. R., Jarrahi, A., Karpowich, K., Moody, E., Renner, L., Brown, L. P., Tressler, C. M., & Crouch, A. C. (2026). Impact of aging on neck vasculature and brain biochemistry in female mice. Physiological Reports, 14(17), Article e71059. https://doi.org/10.14814/phy2.71059

Image Credits: AI Generated

DOI: 10.14814/phy2.71059

Keywords: aging, carotid artery, wall shear stress, arterial stiffness, lipidomics, mass spectrometry imaging, hippocampus, cardiolipin, female mice, neurovascular, sphingolipids, brain biochemistry