KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice

Gupta, Shweta; Moreno, Arturo J.; Wang, Dan; Leon, Julio; Chen, Chen; Hahn, Oliver; Poon, Yan; Greenberg, Kenneth S.; David, Nathaniel E.; Wyss‐Coray, Tony; Raftery, Daniel; Promislow, Daniel; Dubal, Dena B.

doi:10.1523/jneurosci.2458-21.2022

Cited by 14 publications

(16 citation statements)

References 56 publications

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“…For example, increasing the AP Beta-2-microglublin systemically has adverse effects on hippocampal-dependent cognitive functioning and neurogenesis (Smith et al, 2015). Conversely, a cleaved domain of the AP Klotho, KL1, was shown to be sufficient to enhance cognition and to mediate the effects of the complete protein (Gupta et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Markers of aging: Unsupervised integrated analyses of the human plasma proteome

Coenen

Lehallier²,

Vries

et al. 2023

Front. Aging

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Aging associates with an increased susceptibility for disease and decreased quality of life. To date, processes underlying aging are still not well understood, leading to limited interventions with unknown mechanisms to promote healthy aging. Previous research suggests that changes in the blood proteome are reflective of age-associated phenotypes such as frailty. Moreover, experimentally induced changes in the blood proteome composition can accelerate or decelerate underlying aging processes. The aim of this study is to identify a set of proteins in the human plasma associated with aging by integration of the data of four independent, large-scaled datasets using the aptamer-based SomaScan platform on the human aging plasma proteome. Using this approach, we identified a set of 273 plasma proteins significantly associated with aging (aging proteins, APs) across these cohorts consisting of healthy individuals and individuals with comorbidities and highlight their biological functions. We validated the age-associated effects in an independent study using a centenarian population, showing highly concordant effects. Our results suggest that APs are more associated to diseases than other plasma proteins. Plasma levels of APs can predict chronological age, and a reduced selection of 15 APs can still predict individuals’ age accurately, highlighting their potential as biomarkers of aging processes. Furthermore, we show that individuals presenting accelerated or decelerated aging based on their plasma proteome, respectively have a more aged or younger systemic environment. These results provide novel insights in the understanding of the aging process and its underlying mechanisms and highlight potential modulators contributing to healthy aging.

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Section: Discussionmentioning

confidence: 99%

Markers of aging: Unsupervised integrated analyses of the human plasma proteome

Coenen

Lehallier²,

Vries

et al. 2023

Front. Aging

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“…GABA receptor agonist: Liu W, et al, 2021 ; Prud’homme et al, 2017a ; Son et al, 2019 ; Wang Q, et al, 2019 . Recombinant Klotho protein or peptides: Ali et al, 2020 ; Chen TH, et al, 2013 ; Doi et al, 2011 ; Gupta et al, 2022 ; Hu et al, 2017 ; Leon et al, 2017 ; Maltese et al, 2017 ; Mencke et al, 2017 ; Myung et al, 2022 ; Oh et al, 2018 ; Prud’homme et al, 2020 ; Rao Z, et al, 2019 ; Takenaka et al, 2018 , 2019 , 2020 ; Yang et al, 2015 ; Yuan et al, 2022 ; Zhong et al, 2020 . Gene therapy: Arbel Rubinstein et al, 2021 ; Franco et al, 2021 ; Lin & Sun, 2015a , b ; Ni et al, 2021 ; Mencke et al, 2017 ; Shin et al, 2019 ; Xiang et al, 2021 ; Zeng et al, 2019 .…”

Section: Approaches To Klotho-based Therapyunclassified

“…In young and aged mice, systemic delivery of a Klotho-derived peptide that does not cross the BBB improved cognition and reduced neurodegenerative pathology ( Leon et al, 2017 ). Others showed that systemic delivery of either s-Klotho or only the KL1 domain also improved cognition ( Gupta et al, 2022 ). It is unclear how these beneficial Klotho-based effects are mediated, but penetrance into the brain does not appear to be required, and this merits further investigation.…”

Section: Approaches To Klotho-based Therapymentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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“…Testing was carried out as described [12,[21][22][23]. Briefly, the water maze pool (diameter, 122 cm) contained white, opaque water with a square, 14 cm 2 platform submerged 2 cm below the surface.…”

Section: Morris Water-mazementioning

confidence: 99%

X chromosome factor Kdm6a enhances memory independent of its demethylase function in the aging XY male brain

Shaw

Abdulai-Saiku

Marino

et al. 2022

Preprint

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Males exhibit shorter lifespan and more cognitive deficits in aging human populations. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because males show decreased expression of select X factors. While each sex (XX and XY) harbors one active X due to X chromosome inactivation in females, some genes, such as Kdm6a, transcriptionally escape silencing in females – resulting in lower levels in males. Kdm6a is a known histone demethylase (H3K27me2/3) with multiple functional domains that is linked with synaptic plasticity and cognition. Whether elevating Kdm6a could benefit the aging male brain and whether this requires its demethylase function remains unknown. We used lentiviral-mediated overexpression of the X factor in the hippocampus of aging male mice and tested their cognition and behavior in the Morris water maze. We found that acutely increasing Kdm6a – in a form without demethylase function – selectively improved learning and memory, without altering total activity or anxiety-like measures, in the aging XY brain. Further understanding the demethylase-independent downstream mechanisms of Kdm6a may lead to novel therapies for treating age-induced cognitive deficits in both sexes.

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KL1 Domain of Longevity Factor Klotho Mimics the Metabolome of Cognitive Stimulation and Enhances Cognition in Young and Aging Mice

Cited by 14 publications

References 56 publications

Markers of aging: Unsupervised integrated analyses of the human plasma proteome

Markers of aging: Unsupervised integrated analyses of the human plasma proteome

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

X chromosome factor Kdm6a enhances memory independent of its demethylase function in the aging XY male brain

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