Synchrony and asynchrony between an epigenetic clock and developmental timing

Hoshino, Akina; Horvath, Steve; Sridhar, Akshayalakshmi; Chitsazan, Alex; Reh, Thomas A.

doi:10.1038/s41598-019-39919-3

Cited by 42 publications

(45 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For this purpose, we conducted an unbiased screen for epigenetic age acceleration (EAA) in samples from patients with developmental disorders that we could access and for which genome-wide DNA methylation data was available (Table 1, Additional file 2). Horvath’s epigenetic clock, unlike other epigenetic clocks available in the literature, works across the entire human lifespan (even in prenatal samples), and it is therefore well suited for this type of analysis [5, 8, 32]. All the DNA methylation data were generated from the blood using the Illumina HumanMethylation450 array (450K array).…”

Section: Resultsmentioning

confidence: 99%

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1

et al. 2019

View full text Add to dashboard Cite

Background Epigenetic clocks are mathematical models that predict the biological age of an individual using DNA methylation data and have emerged in the last few years as the most accurate biomarkers of the aging process. However, little is known about the molecular mechanisms that control the rate of such clocks. Here, we have examined the human epigenetic clock in patients with a variety of developmental disorders, harboring mutations in proteins of the epigenetic machinery. Results Using the Horvath epigenetic clock, we perform an unbiased screen for epigenetic age acceleration in the blood of these patients. We demonstrate that loss-of-function mutations in the H3K36 histone methyltransferase NSD1, which cause Sotos syndrome, substantially accelerate epigenetic aging. Furthermore, we show that the normal aging process and Sotos syndrome share methylation changes and the genomic context in which they occur. Finally, we found that the Horvath clock CpG sites are characterized by a higher Shannon methylation entropy when compared with the rest of the genome, which is dramatically decreased in Sotos syndrome patients. Conclusions These results suggest that the H3K36 methylation machinery is a key component of the epigenetic maintenance system in humans, which controls the rate of epigenetic aging, and this role seems to be conserved in model organisms. Our observations provide novel insights into the mechanisms behind the epigenetic aging clock and we expect will shed light on the different processes that erode the human epigenetic landscape during aging. Electronic supplementary material The online version of this article (10.1186/s13059-019-1753-9) contains supplementary material, which is available to authorized users.

show abstract

Section: Resultsmentioning

confidence: 99%

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1

et al. 2019

View full text Add to dashboard Cite

show abstract

“…We did not observe age deceleration in postmortem brain samples of the human cortex, indicating the the observe signal may be blood-specific. Horvath DNAm aging has been shown to associate with molecular processes of development and cell differentiation 12,32 , including human (neuro)developmental phenotypes 45,46 . Our findings may indicate that individuals diagnosed with SCZ in this age group show evidence of delayed or deficient development and that this is detectable in blood through the multi-tissue Horvath clock.…”

Section: Discussionmentioning

confidence: 99%

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

Ori

Loohuis

Guintivano

et al. 2019

Preprint

Self Cite

View full text Add to dashboard Cite

Schizophrenia (SCZ) is a severe mental illness that is associated with an increased prevalence of age-related disability and morbidity compared to the general population. An accelerated aging process has therefore been hypothesized as a component of the SCZ disease trajectory. Here, we investigated differential aging using three DNA methylation (DNAm) clocks (i.e. Hannum, Horvath, Levine) in a multi-cohort SCZ whole blood sample consisting of 1,100 SCZ cases and 1,200 controls. It is known that all three DNAm clocks are highly predictive of chronological age and capture different features of biological aging.We found that blood-based DNAm aging is significantly altered in SCZ with age-and sexspecific effects that differ between clocks and map to distinct chronological age windows.Most notably, the predicted phenotypic age (Levine clock) in female cases, starting at age 36 and beyond, is 3.21 years older compared to matching control subjects (95% CI: 1.92-4.50, P=1.3e-06) explaining 7.7% of the variance in disease status. Female cases with high SCZ polygenic risk scores present the highest age acceleration in this age group with +7.03 years (95% CI: 3.87-10.18, P=1.7E-05). Since increased phenotypic age is associated with increased risk of all-cause mortality, our findings suggests that specific and identifiable patient groups are at increased mortality risk as measured by the Levine clock. These results provide new biological insights into the aging landscape of SCZ with age-and sexspecific effects and warrant further investigations into the potential of DNAm clocks as clinical biomarkers that may help with disease management in schizophrenia.

show abstract

“…We can only begin to address this question after having first understood what epigenetic aging entails. As it stands, our knowledge in this area remains limited, but it is nevertheless clear that: (a) epigenetic aging is distinct from the process of cellular senescence and telomere attrition 41 , (b) several types of tissue stem cells are epigenetically younger than non-stem cells of the same tissue 42,43 , (c) a considerable number of age-related methylation sites, including some clock CpGs, are proximal to genes whose proteins are involved in the process of development 44 , (d) epigenetic clocks are associated with developmental timing 22,45 , and (e) relate to an epigenomic maintenance system 20,46 . Collectively, these features indicate that epigenetic aging is intimately associated with the process of development and homeostatic maintenance of the body post-maturity.…”

Section: Plasma Fraction Treatmentmentioning

confidence: 99%

Reversing age: dual species measurement of epigenetic age with a single clock

Horvath

Singh

Raj

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.

show abstract

Synchrony and asynchrony between an epigenetic clock and developmental timing

Cited by 42 publications

References 57 publications

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1

Screening for genes that accelerate the epigenetic aging clock in humans reveals a role for the H3K36 methyltransferase NSD1

Epigenetic age is accelerated in schizophrenia with age- and sex-specific effects and associated with polygenic disease risk

Reversing age: dual species measurement of epigenetic age with a single clock

Contact Info

Product

Resources

About