Klotho and the Thread of Life – Can We Delay Aging?




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In Greek mythology, the Fates, or Moirae, were the goddesses who controlled humans’ destiny, from the time they were born to the time they died. The three sisters, Clotho, Lachesis and Atropos, daughters of Zeus and Themis, controlled the thread of human life.

Each Fate had a task: Lachesis was the apportioner, she measured the thread and decided how much lifetime was to be allowed; Atropos, the inevitable, cut the thread choosing when mortals would die; Clotho was the spinner, she spun the thread of a person’s life.

Clotho was the inspiration for naming klotho – a gene that somehow also seems to spin the thread of life. Klotho was another of so many serendipitous discoveries in science: while studying the phenotype of transgenic mice overexpressing another gene, there was an accidental insertion of ectopic DNA in a region of the klotho gene, inhibiting its expression. Makoto Kuro-o and colleagues, from the National Institute of Neuroscience, in Tokyo, Japan, thus found, in 1997, that disruption of the klotho gene caused accelerated aging. Later, it was found that the opposite also happened: by overexpressing klotho in mice, aging was significantly delayed and a longer lifespan was acquired.

The Journal of Neuroscience’s February article, showing that klotho can decrease premature mortality and enhance spatial learning and memory in a mouse model of Alzheimer’s disease piqued my curiosity about this protein. Obviously, the discovery of klotho generated massive research interest – a protein that may stop aging is the Holy Grail of life sciences, I reckon.

But how much is known about klotho? Can it really delay aging in humans?

Although the discovery of klotho has boosted the understanding of the aging process, its function is still not fully understood. In humans, serum levels of klotho decrease with age after 40 years old. This decrease is also observed in patients with several aging-related diseases. But most of what is known so far comes from animal research studies.

Although klotho is mainly produced in the kidneys and in the brain choroid plexus, mutations to its gene cause widespread aging phenotypes, probably due to circulating klotho. Deficiency has been associated with hypertension, renal failure, decreased insulin production and increased insulin sensitivity, early diabetic nephropathy, ectopic calcification in various soft tissues, arteriosclerosis, among others. Increased klotho expression, on the other hand, has been linked to reduced tumor proliferation and anti-inflammatory effects. In the brain, klotho deficiency in mice induced memory deficits, hippocampus degeneration, a reduction in synapses, and impaired axonal transport and myelin production.

Most of these phenotypes seem to be associated with defective calcium metabolism. Klotho seems to be essential in the maintenance of the levels of calcium and phosphorus by negatively regulating the synthesis of active vitamin D; abnormal activation of vitamin D due to klotho insufficiency has actually been shown to lead to degeneration of the dopaminergic system associated with Parkinson’s disease. Klotho also seems to act by increasing the expression of antioxidant enzymes and conferring resistance to oxidative stress, known to cause significant DNA damage.

Klotho and neurodegeneration

Myelin is an insulating material that envelops neurons, being essential for the correct functioning of the nervous system. Altered myelin production is a characteristic of the normal aging process of the brain. In fact, age-related cognitive decline seems to be mostly associated with loss of myelin rather than loss of neurons. There are experimental evidences suggesting that klotho is a key regulator in myelin biology by promoting and maintaining myelination. Therefore, it is possible that the loss of klotho expression may account for the age-related cognitive decline through decreased myelin production.

This link between cognitive decline, myelin abnormalities and klotho downregulation places it as a potential therapeutic target for neuroprotection against myelin-associated age-dependent changes. Compounds that increase klotho expression may therefore become important therapeutic tools for the treatment of neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease. Increasing klotho levels may protect myelin integrity and prevent myelin degeneration in the aged brain and promote repair in multiple sclerosis.

This may be quite a wondrous molecule.

Maybe one day we will use klotho to prevent neurodegeneration and keep our brains young. Could we carry out a body transplant when our bodies get old, and use our cloned, younger body? Too much science fiction? Probably. But we once thought we couldn’t go to the Moon.

References

Abraham CR, Chen C, Cuny GD, Glicksman MA, & Zeldich E (2012). Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Future medicinal chemistry, 4 (13), 1671-9 PMID: 22924505

Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, & Abraham CR (2013). The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (5), 1927-39 PMID: 23365232

Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-O M, Masliah E, Abraham CR, & Mucke L (2015). Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 35 (6), 2358-71 PMID: 25673831

Kosakai A, Ito D, Nihei Y, Yamashita S, Okada Y, Takahashi K, & Suzuki N (2011). Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure. Brain research, 1382, 109-17 PMID: 21276773

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 (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature, 390 (6655), 45-51 PMID: 9363890

Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, & Kuro-o M (2005). Suppression of aging in mice by the hormone Klotho. Science (New York, N.Y.), 309 (5742), 1829-33 PMID: 16123266

Nabeshima Y (2002). Klotho: a fundamental regulator of aging. Ageing research reviews, 1 (4), 627-38 PMID: 12362891

Xu Y, & Sun Z (2015). Molecular Basis of Klotho: From Gene to Function in Aging. Endocrine reviews PMID: 25695404

Image via Twin Design / Shutterstock.

Sara Adaes, PhD

Sara Adaes, PhD, has been a researcher in neuroscience for over a decade. She studied biochemistry and did her first research studies in neuropharmacology. She has since been investigating the neurobiological mechanisms of pain at the Faculty of Medicine of the University of Porto, in Portugal. Follow her on Twitter @saradaes
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