top of page
Search

Klotho: The Longevity Gene

By Shannon Kasun, Neuroscience Specialist


ree

Many people are familiar with the so-called “Alzheimer’s gene,” ApoE4. Carrying one copy of this variant (allele) increases the risk of Alzheimer’s disease two to three times, while two copies can raise risk up to twelvefold. With global cases projected to reach 150 million by 2050, researchers have been searching for genetic factors that might counteract this vulnerability—genes that could promote resilience and support healthy brain aging.


One promising candidate is Klotho. Discovered in 1997, Klotho takes its name from Clotho, one of the three Fates in Greek mythology. Clotho spun the thread of human life, while her sisters measured and cut it, determining a person’s lifespan. The name proved fitting: mice bred without Klotho aged rapidly and died young, while higher Klotho levels extended lifespan (Kurosu et al., 2005). In many ways, Klotho weaves the biological pathways that shape how long—and how well—we live.


Now often called the “longevity gene,” Klotho influences many of the systems disrupted by aging: metabolism, oxidative stress, mineral balance, inflammation, and brain health. For example, Klotho helps quiet down insulin and IGF-1, two signals that push the body into “growth mode.” By turning down these pathways, the body shifts toward cellular cleanup, repair, and resilience—an evolutionarily conserved survival strategy that once helped our ancestors endure food scarcity (Kurosu et al., 2005). Klotho also helps calm inflammation by suppressing NF-κB, a major driver of chronic low-grade inflammation with age (Nakao et al., 2022).


Certain variants of the Klotho gene, such as KL-VS, boost production of the protein and have been linked to larger brain volume and stronger cognitive performance, potentially helping offset age-related brain shrinkage (atrophy) and cognitive decline (Yokoyama et al., 2015). This protective effect may be especially important for people carrying ApoE4. In fact, pretreatment with Klotho protein has been shown to protect the hippocampus—the brain region most vulnerable to Alzheimer’s disease—from amyloid-beta and glutamate toxicity, highlighting its therapeutic potential in neurodegeneration (Abraham et al., 2016).


Taken together, Klotho represents one of the most compelling resilience factors in aging biology. By reducing harmful signals, calming inflammation, and supporting brain function, it offers a powerful counterbalance to genetic risks like ApoE4. Even more encouraging: lifestyle choices matter. Regular aerobic exercise has been shown to boost circulating Klotho levels, reminding us that our genes are not our absolute destiny—we have a say in how we age  (Ji et al., 2018). While research and therapies are still developing, strategies to support Klotho—especially through movement—should be considered a staple in any longevity toolkit, helping us pursue not just longer life, but better life.


References 


Kurosu, Hiroshi et al. “Suppression of aging in mice by the hormone Klotho.” Science (New York, N.Y.) vol. 309,5742 (2005): 1829-33. doi:10.1126/science.1112766 


Nakao, Vinicius Wanatable et al. “Neuroprotective action of α-Klotho against LPS-activated glia conditioned medium in primary neuronal culture.” Scientific reports vol. 12,1 18884. 7 Nov. 2022, doi:10.1038/s41598-022-21132-4

Yokoyama, Jennifer S et al. “Variation in longevity gene KLOTHO is associated with greater cortical volumes.” Annals of clinical and translational neurology vol. 2,3 (2015): 215-30. doi:10.1002/acn3.161 


Abraham, C R et al. “Klotho Is a Neuroprotective and Cognition-Enhancing Protein.” Vitamins and hormones vol. 101 (2016): 215-38. doi:10.1016/bs.vh.2016.02.004


Ji, Naichun et al. “Aerobic exercise-stimulated Klotho upregulation extends life span by attenuating the excess production of reactive oxygen species in the brain and kidney.” Experimental and therapeutic medicine vol. 16,4 (2018): 3511-3517. doi:10.3892/etm.2018.6597

 
 
 

Comments

bottom of page