Brain & Neurons

Study Suggest Anti-Aging Protein Mimics Mental Stimulation in Mice

UCSF scientists find that the anti-aging protein klotho counters memory deficiencies in aged mice and activates metabolites associated with cognitive stimulation.

By Daniel R. Miranda, Ph.D.

Key points: 

  • Treating aged mice with the anti-aging protein klotho improves their spatial and short-term memory. 
  • Klotho and cognitive stimulation activate overlapping metabolites in young mice, suggesting that klotho mimics cognitive stimulation. 

Klotho was named after one of the Fates, the Greek goddess Clotho, who spins the thread of life. It was named so by scientists because mice without klotho age faster and have shortened lifespans. Furthermore, humans with higher levels of klotho tend to live longer. Now, what if this protein could mimic the benefits of cognitive stimulation, which is associated with a reduced risk of Alzheimer’s?

Gupta and colleagues from the University of California, San Francisco report in the Journal of Neuroscience that treating mice with klotho mimics the metabolic changes associated with cognitive stimulation and counters age-related cognitive deficits.  

Klotho Improves the Memory of Aged Mice

To test the effect of klotho on the cognitive performance of aged mice, Gupta and colleagues subjected aged mice to the Y maze, a test for measuring spatial and short-term memory. Investigators found that 22-month-old mice (equivalent to about 70 human years) injected with a mouse variant of klotho (mKL1) were more apt to explore new areas of the maze compared to untreated aged mice, suggesting that klotho improves the spatial and short-term memory of aged mice.

(Gupta et al., 2022 | The Journal of Neuroscience) Klotho Improves the Memory of Aged Mice. (H) Aged mice were injected with 10 µg/kg of mKL1 or a solution without mKL1 (Veh), trained 24 hours later on the Y-maze, and tested 40 hours later. (I) During the test, mKL1-treated mice showed an increased preference for the novel arm of the maze compared to the familiar arm, suggesting improved memory. 

To determine which metabolites are activated in response to cognitive stimulation, Gupta and colleagues removed the brains of young mice (4 months old, equivalent to 26 human years) after completing the Y-maze test to analyze the genes activated in their hippocampus — the brain region that consolidates memories. Compared to non-cognitively stimulated mice, which were mice placed into an ordinary cage before brain harvesting, cognitively stimulated mice had altered metabolite levels. Several of these metabolites are known to decrease with aging and are associated with neurodegeneration.

To examine the effect of klotho on these metabolites, mice were injected with a long (KL) or short (KL1) variant of the klotho protein. It was found that several of the metabolites altered by KL and KL1 overlapped with the metabolites altered by cognitive stimulation. A total of six metabolites overlapped between all three groups. Thus, the data suggest that in the absence of cognitive tasks, klotho causes metabolic alterations that partially mimic a cognitively stimulated brain.

(Gupta et al., 2022 | The Journal of Neuroscience) Klotho Mimics Cognitive Stimulation. Of the metabolites altered by cognitive stimulation and both variants of klotho (KL and KL1), six overlapped, as shown in the Venn diagram. Each metabolite is associated with a cellular pathway, many of which are associated with protein metabolism and the metabolism of purines, chemical components of DNA.

Overall, the findings of Gupta and colleagues suggest that klotho can improve the cognitive performance of aged mice and mimic cognitive stimulation in young mice. The implications of these findings allude to klotho as a potential cognitive enhancer for both the young and old. However, klotho has not yet been tested for this purpose and is not available in supplement form. 

Why Care about Klotho?

Low klotho levels have been associated with a 31% higher risk of death in American adults aged 40 to 79 years.  Additionally, individuals within the same age range who suffer from metabolic syndrome were observed to have low klotho levels. Furthermore, previous studies have shown that low klotho levels are associated with cardiovascular and kidney disease

While klotho research hasn’t reached the clinical stage, there are some recent studies showing how it can be boosted. Although still under peer review, an analysis of 12 studies showed that 621 individuals ranging from the ages of 30 to 65 had increased levels of klotho after 12 weeks of exercise, regardless of their health condition. This would suggest that klotho levels can be boosted by regular exercise, possibly enhancing cognitive performance. Indeed, another analysis of several studies showed that increasing klotho with aerobic exercise is associated with improving cognition in Alzheimer’s patients

In addition to exercise, a Mayo Clinic study showed that a combination of dasatinib and quercetin, which are senolytic compounds, boost klotho levels in aged and obese mice. Moreover, a recent study showed that a molecule called berberine, which has been shown to extend the lifespan of fruit flies and mice, also raises klotho levels in aged mice and protects the heart against age-related damage. Since senolytics, berberine, and exercise all slow down the aging process and raise klotho levels, it would seem that klotho was appropriately named. 


Gupta S, Moreno AJ, Wang D, Leon J, Chen C, Hahn O, Poon Y, Greenberg K, David N, Wyss-Coray T, Raftery D, Promislow DEL, Dubal DB. KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice. J Neurosci. 2022 May 11;42(19):4016-4025. doi: 10.1523/JNEUROSCI.2458-21.2022. Epub 2022 Apr 15. PMID: 35428698; PMCID: PMC9097772.



Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997 Nov 6;390(6655):45-51. doi: 10.1038/36285. PMID: 9363890.


Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC. Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):856-61. doi: 10.1073/pnas.022484299. Epub 2002 Jan 15. PMID: 11792841; PMCID: PMC117395.


Wilson RS, Mendes De Leon CF, Barnes LL, Schneider JA, Bienias JL, Evans DA, Bennett DA. Participation in cognitively stimulating activities and risk of incident Alzheimer disease. JAMA. 2002 Feb 13;287(6):742-8. doi: 10.1001/jama.287.6.742. PMID: 11851541.


Kresovich JK, Bulka CM. Low Serum Klotho Associated With All-cause Mortality Among a Nationally Representative Sample of American Adults. J Gerontol A Biol Sci Med Sci. 2022 Mar 3;77(3):452-456. doi: 10.1093/gerona/glab308. PMID: 34628493; PMCID: PMC9122743.


Orces CH. The association between metabolic syndrome and the anti-aging humoral factor klotho in middle-aged and older adults. Diabetes Metab Syndr. 2022 Jun;16(6):102522. doi: 10.1016/j.dsx.2022.102522. Epub 2022 May 27. PMID: 35660935.


Semba RD, Cappola AR, Sun K, Bandinelli S, Dalal M, Crasto C, Guralnik JM, Ferrucci L. Plasma klotho and cardiovascular disease in adults. J Am Geriatr Soc. 2011 Sep;59(9):1596-601. doi: 10.1111/j.1532-5415.2011.03558.x. Epub 2011 Aug 24. PMID: 21883107; PMCID: PMC3486641.


Kim HJ, Lee J, Chae DW, Lee KB, Sung SA, Yoo TH, Han SH, Ahn C, Oh KH. Serum klotho is inversely associated with metabolic syndrome in chronic kidney disease: results from the KNOW-CKD study. BMC Nephrol. 2019 Apr 3;20(1):119. doi: 10.1186/s12882-019-1297-y. PMID: 30943913; PMCID: PMC6446407.


Gaitán JM, Moon HY, Stremlau M, Dubal DB, Cook DB, Okonkwo OC, van Praag H. Effects of Aerobic Exercise Training on Systemic Biomarkers and Cognition in Late Middle-Aged Adults at Risk for Alzheimer’s Disease. Front Endocrinol (Lausanne). 2021 May 20;12:660181. doi: 10.3389/fendo.2021.660181. PMID: 34093436; PMCID: PMC8173166.


Li C, Jiang S, Wang H, Wang Y, Han Y, Jiang J. Berberine exerts protective effects on cardiac senescence by regulating the Klotho/SIRT1 signaling pathway. Biomed Pharmacother. 2022 Jul;151:113097. doi: 10.1016/j.biopha.2022.113097. Epub 2022 May 24. PMID: 35609366.


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