Klotho: An emerging factor in neurodegenerative diseases

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…61,70,71,74,[77][78][79][80] Manifestations of OS are hallmark symptoms in neurological disease, including cognitive deficits. 52,54,65,76,79,[81][82][83][84][85][86][87][88] In concert with the above, a correlation was found between OS in the CNS and demyelination, which results in the loss of integrity and proper maintenance of oligodendrocytes and their myelin sheaths, the latter being crucial for cognitive performance and higher brain function. 57,[89][90][91] Thus, inclusion of strategies for enhancing mitochondrial biogenesis, function, and protection 68,80,[92][93][94][95][96] that may also rely on pathways epigenetically induced by diet [97][98][99][100][101][102][103][104][105][106][107][108] and/or exercise 99,100,…”

“…48 In addition to AD, the most common neurodegenerative disease, Parkinson's disease (PD), the second most common neurodegenerative disease, 49 has also been tied to Klotho pathways. [50][51][52] Beyond AD and PD, age-related declines in Klotho 8,13,17,24,53 are associated with a range of other deteriorating central nervous system (CNS) processes. 17,24 For example, mounting evidence implicates dysregulation of Klotho in shared mechanistic pathological relationships linking iron and myelin in various common and rare brain diseases, [54][55][56] including abnormalities in myelination and the maturation of oligodendrocytes that are central to the pathogenicity of diseases such as multiple sclerosis (MS) 26,56,57 and amyotrophic lateral sclerosis (ALS).…”

“…5,6,137,141,[144][145][146][147][148] In particular, FGF23 is a bone-derived hormone that in conjunction with Klotho acts on the kidney to increase phosphate excretion and suppress biosynthesis of vitamin D. 5,6,14,23,102,136,138,145,148,149 Vitamin D regulates epigenetic mechanisms that maintain the transcription of its target genes in regulatory networks, including the expression of Klotho and nuclear factor-erythroid-2related factor 2 (Nrf2) to carry out many of its homoeostatic functions. 17,97,[150][151][152][153] Vitamin D is a modulator of the immune system, 154,155 hence its mention here, and accumulating evidence suggests vitamin D deficiency is a risk factor for dysregulated Klotho-associated neurodegenerative diseases, the most noteworthy being MS. 9,27,52,97,102,150,152,153,[156][157][158] Multiple Sclerosis MS is an insidious progressive neurodegenerative disease characterized by demyelinated lesions throughout the brain, spinal cord, and optic nerve resulting from immune-mediated attacks against myelin. [159][160][161]…”

“…3,18,27,102,183,184 A soluble form of Klotho (sKlotho), primarily secreted from the kidney, circulates in blood, urine, and cerebrospinal fluid, exerting different biological effects in multiple tissues as a humoral factor. 5,6,8,52,[185][186][187][188][189] In the eye, Klotho protects against OS 53,55,58,153,190,191 and is essential to the proper maintenance and function of the ocular system, 12,26,[192][193][194][195] being expressed throughout the retina, with the highest levels in retinal ganglion cells. 196 The retinal pigment epithelium (RPE) is a highly specialized CNS tissue whose function is critical in preserving retinal homeostasis 53,78 and an age-dependent decline of Klotho expression is said to contribute to RPE degeneration and retinal pathology.…”

Birth size and the pace of aging in men

“…There are many physiological markers of biological age, including speci c proteins, hormones, oxidative stress, or in ammation level. One such speci c protein is α-Klotho which level is positively associated with slowing the aging process and longevity [33][34][35][36], and negatively with the risk of neurodegenerative disease [37], hypertension [38], triglycerides levels [39], and chronic in ammation [40]. Polymorphism of the gene encoding α-Klotho has also been shown to be related to healthy aging [41], risk of dementia [42], all-cause mortality [43], or risk of prostate cancer [44].…”