DNA methylation age analysis of rapamycin in common marmosets

Horvath, Steve; Zoller, Joseph A.; Haghani, Amin; Lu, Ake T.; Raj, Ken; Jasinska, Anna J.; Mattison, Julie A.; Salmon, Adam B.

doi:10.1007/s11357-021-00438-7

Cited by 26 publications

(8 citation statements)

References 48 publications

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“…In fact, the fascinating evidence that even the primary transcript of α-syn was decreased by rapamycin administration opens novel pathways through which mTOR suppression may act at an epigenetic level. The epigenetics of rapamycin is likely to involve a number of loci and may be key in remodeling cell biology [63,64]. These data help to contextualize novel evidence to foster dedicated investigations.…”

Section: Discussionmentioning

confidence: 95%

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Ryskalin

Ferese

Morucci

et al. 2022

Cancers

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Alpha-synuclein (α-syn) is a protein considered to be detrimental in a number of degenerative disorders (synucleinopathies) of which α-syn aggregates are considered a pathological hallmark. The clearance of α-syn strongly depends on autophagy, which can be stimulated by inhibiting the mechanistic target of rapamycin (mTOR). Thus, the overexpression of mTOR and severe autophagy suppression may produce α-syn accumulation, including the proteinase K-resistant protein isoform. Glioblastoma multiforme (GBM) is a lethal brain tumor that features mTOR overexpression and severe autophagy inhibition. Cell pathology in GBM is reminiscent of a fast, progressive degenerative disorder. Therefore, the present work questions whether, as is analogous to neurons during degenerative disorders, an overexpression of α-syn occurs within GBM cells. A high amount of α-syn was documented in GBM cells via real-time PCR (RT-PCR), Western blotting, immunohistochemistry, immuno-fluorescence, and ultrastructural stoichiometry, compared with the amount of β- and γ-synucleins and compared with the amount of α-syn counted within astrocytes. The present study indicates that (i) α-syn is overexpressed in GBM cells, (ii) α-syn expression includes a proteinase-K resistant isoform, (iii) α-syn is dispersed from autophagy-like vacuoles to the cytosol, (iv) α-syn overexpression and cytosol dispersion are mitigated by rapamycin, and (v) the α-syn-related GBM-like phenotype is mitigated by silencing the SNCA gene.

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Section: Discussionmentioning

confidence: 95%

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Ryskalin

Ferese

Morucci

et al. 2022

Cancers

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“…Age deceleration -defined here as a lower BA relative to CA-in mice was observed in response to treatment with rapamycin (Wang et al, 2017), an immunosuppressant drug with a well-established ability to boost longevity (Bitto et al, 2016). Intriguingly, rapamycin was not associated with a significantly reduced epigenetic age in a separate study done in marmoset monkeys (Horvath et al, 2021). Whether or not this is due to the concentration of rapamycin, treatment duration, the specific clocks used, or differences between mice and marmosets remains to be determined.…”

Section: Aging Clocks Are Targetable In Complex Animalsmentioning

confidence: 90%

“…One explanation for the differential results may be the disparate tissues analyzed. Measurements were made in liver and blood for mice (Wang et al, 2017) and marmosets (Horvath et al, 2021), respectively. Genetic mutations or gene therapy are discrete paths towards slowing an animal's molecular clock.…”

Section: Aging Clocks Are Targetable In Complex Animalsmentioning

confidence: 99%

Human age reversal: Fact or fiction?

et al. 2022

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Although chronological age correlates with various age‐related diseases and conditions, it does not adequately reflect an individual's functional capacity, well‐being, or mortality risk. In contrast, biological age provides information about overall health and indicates how rapidly or slowly a person is aging. Estimates of biological age are thought to be provided by aging clocks, which are computational models (e.g., elastic net) that use a set of inputs (e.g., DNA methylation sites) to make a prediction. In the past decade, aging clock studies have shown that several age‐related diseases, social variables, and mental health conditions associate with an increase in predicted biological age relative to chronological age. This phenomenon of age acceleration is linked to a higher risk of premature mortality. More recent research has demonstrated that predicted biological age is sensitive to specific interventions. Human trials have reported that caloric restriction, a plant‐based diet, lifestyle changes involving exercise, a drug regime including metformin, and vitamin D3 supplementation are all capable of slowing down or reversing an aging clock. Non‐interventional studies have connected high‐quality sleep, physical activity, a healthy diet, and other factors to age deceleration. Specific molecules have been associated with the reduction or reversal of predicted biological age, such as the antihypertensive drug doxazosin or the metabolite alpha‐ketoglutarate. Although rigorous clinical trials are needed to validate these initial findings, existing data suggest that aging clocks are malleable in humans. Additional research is warranted to better understand these computational models and the clinical significance of lowering or reversing their outputs.

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“…Epigenetic clocks have been developed for several NHPs including rhesus macaque and marmoset [27,28] but not yet for the vervet monkey. The vervet monkey (genus Chlorocebus) is an Old World monkey frequently used as a model in biomedical research [1,6] particularly for complex chronic diseases, many of which either are associated with aging or aggravate the process of aging.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic clock and methylation studies in vervet monkeys

et al. 2021

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DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, we developed two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes that gain methylation with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for anti-aging studies in vervets.

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DNA methylation age analysis of rapamycin in common marmosets

Cited by 26 publications

References 48 publications

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Occurrence of Total and Proteinase K-Resistant Alpha-Synuclein in Glioblastoma Cells Depends on mTOR Activity

Human age reversal: Fact or fiction?

Epigenetic clock and methylation studies in vervet monkeys

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