Tier 3 — preclinical

Fisetin Reduces the Impact of Aging on Behavior and Physiology in the Rapidly Aging SAMP8 Mouse

Antonio Currais, Catherine Farrokhi, Richard Dargusch, Aaron Armando, Oswald Quehenberger, David Schubert, Pamela Maher

Journals of Gerontology: Biological Sciences 2018 Vol. 73, No. 3, pages 299–307

Bibliography

DOI: 10.1093/gerona/glx104
PubMed: PMID 28575152
PubMed Central: PMC5861950
Funding: This work was supported by the Salk Institute Pioneer Fund Postdoctoral Scholar Award and the Salk Nomis Fellowship Award to AC and grants from the Alzheimer's Association, Burns Foundation, and National Institutes of Health (grant numbers RO1AG046153, RO1AG035055, and R42A1104034) to PM and DS. This work was also supported by a NINDS Neuroscience Core Grant for the Behavioral Testing Core Facility.
Competing interests: The authors have no conflicts of interest.

Study snapshot

Design	Preclinical in vivo animal study
Model	Senescence-accelerated prone 8 (SAMP8) mice
Sample	49 male SAMP8 mice (17 control diet, 18 fisetin diet, 14 young controls)
Intervention	Fisetin diet (500 ppm, approximately 25 mg/kg/day)
Duration	7 months
Endpoints	Cognitive function (spatial learning, short-term recognition memory, disinhibition); locomotor activity, synaptic protein expression, stress responses (heat shock proteins); inflammation markers (GFAP, SAPK/JNK, microglia, eicosanoids), and global metabolomics

What the study showed, in plain terms

Alzheimer's disease and other forms of dementia are deeply tied to the biological process of aging, marked by mounting cellular stress, inflammation, and a loss of healthy brain chemistry over time. Because these conditions involve multiple overlapping causes, treatments targeting just one specific pathway have historically failed.

In this study, researchers investigated the natural flavonoid fisetin using a specialized breed of mice (SAMP8) that rapidly develops aging and dementia-like symptoms. The researchers fed these mice a fisetin-enriched diet for seven months and compared their memory, behavior, and brain tissue health to both untreated old mice and healthy young mice.

The findings revealed that a long-term fisetin diet successfully prevented age-related cognitive decline, allowing the old mice to learn and remember just as well as the young ones. Fisetin achieved this by restoring essential proteins needed for nerve communication, significantly lowering brain inflammation, and maintaining healthy levels of critical brain fats, including the omega-3 fatty acid DHA.

Key findings

Cognitive Preservation: Fisetin prevented age-related deficits in spatial memory and recognition, enabling old treated mice to perform on par with young healthy mice.
Synaptic Health: The treatment restored the expression of key synaptic proteins (Arc, Homer, SAP102) that are necessary for learning and memory but typically decline with age.
Reduced Brain Inflammation: Fisetin significantly lowered multiple markers of neuroinflammation, including astrocyte activation (GFAP) and pro-inflammatory lipid mediators.
Metabolic Balance: The intervention preserved healthy levels of critical brain metabolites, notably increasing the levels of the essential omega-3 fatty acid DHA while reducing its harmful oxidized byproducts.

What this study can and cannot tell us

Preclinical Animal Model: The study relies on a rapidly aging mouse strain (SAMP8), so the findings must be carefully translated and validated in human clinical trials to confirm efficacy for sporadic Alzheimer's disease.
Preventative Design: Fisetin was administered starting at 3 months of age (before significant decline) over a long duration (7 months). It remains unclear if it could reverse cognitive deficits once symptoms are already fully established.