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A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status.

Sood S, Gallagher IJ, Lunnon K, Rullman E, Keohane A, Crossland H, Phillips BE, Cederholm T, Jensen T, van Loon LJ, Lannfelt L, Kraus WE, Atherton PJ, Howard R, Gustafsson T, Hodges A, Timmons JA - Genome Biol. (2015)

Bottom Line: Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity.We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample.This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.

View Article: PubMed Central - PubMed

Affiliation: XRGenomics Ltd, London, UK.

ABSTRACT

Background: Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health.

Results: One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83-0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is 'up-regulated' in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case-control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA 'disease signature', the healthy ageing RNA classifier is diagnostic for AD.

Conclusions: We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.

No MeSH data available.


Related in: MedlinePlus

The healthy ageing RNA signature in healthy human brain tissue and blood of AD patients and controls. There was robust regulation of the healthy ageing RNA signature in human brain with healthy ageing and between control subjects and subjects with AD or MCI. a The healthy ageing RNA signature was studied across brain regions in healthy individuals using BrainEac.org gene-chip resource [GEO:GSE60862]. Ten brain regions from 134 subjects representing 1231 samples were individually ranked (see “Materials and methods”) and the median sum of the ranked scores calculated. Regulation of the healthy ageing genes differed across brain regions with age, as determined by a Kruskal Wallis Test (hippocampus p = 0.00000002, putamen p = 0.00000004, thalamus p = 0.00004, temporal cortex p = 0.0001, substantia nigra p = 0.0002, frontal cortex p = 0.001, occipital cortex p = 0.001, white matter p = 0.01, medulla p = 0.06 and cerebellar cortex p = 0.51). Post hoc Mann–Whitney test, with correction for multiple comparisons (Holm), confirmed a striking ‘increase’ of the healthy ageing score in the healthy older samples (hippocampus, putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions; at least p < 0.002). b The healthy ageing RNA signature was studied in blood samples from two independently processed case–control studies of AD. In cohort 1 the control median gene score was greater (p = 0.004) than AD samples and greater (p = 0.00005) than that of the MCI samples (Wilcoxon rank sum test). In cohort 2 the median gene score of control samples was greater than that of AD samples (p = 0.009) and that of MCI samples (p = 0.003). Data are median gene score and standard error
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Fig4: The healthy ageing RNA signature in healthy human brain tissue and blood of AD patients and controls. There was robust regulation of the healthy ageing RNA signature in human brain with healthy ageing and between control subjects and subjects with AD or MCI. a The healthy ageing RNA signature was studied across brain regions in healthy individuals using BrainEac.org gene-chip resource [GEO:GSE60862]. Ten brain regions from 134 subjects representing 1231 samples were individually ranked (see “Materials and methods”) and the median sum of the ranked scores calculated. Regulation of the healthy ageing genes differed across brain regions with age, as determined by a Kruskal Wallis Test (hippocampus p = 0.00000002, putamen p = 0.00000004, thalamus p = 0.00004, temporal cortex p = 0.0001, substantia nigra p = 0.0002, frontal cortex p = 0.001, occipital cortex p = 0.001, white matter p = 0.01, medulla p = 0.06 and cerebellar cortex p = 0.51). Post hoc Mann–Whitney test, with correction for multiple comparisons (Holm), confirmed a striking ‘increase’ of the healthy ageing score in the healthy older samples (hippocampus, putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions; at least p < 0.002). b The healthy ageing RNA signature was studied in blood samples from two independently processed case–control studies of AD. In cohort 1 the control median gene score was greater (p = 0.004) than AD samples and greater (p = 0.00005) than that of the MCI samples (Wilcoxon rank sum test). In cohort 2 the median gene score of control samples was greater than that of AD samples (p = 0.009) and that of MCI samples (p = 0.003). Data are median gene score and standard error

Mentions: Neurocognitive pathology (e.g., AD) becomes more pronounced with age and is often apparent in individuals who are otherwise healthy. Our analysis of the relationship between lifestyle factors and the healthy ageing gene score in the ULSAM cohort suggested that the gene score was robust to confounding effects of lifestyle disease. We next examined whether the healthy ageing gene score (median rank sum of the 150 RNA markers) was selectively useful in relation to identifying neurocognitive disease over lifestyle disease. To support this analysis, we utilized a large publically available gene-chip data set derived from healthy human brain samples of various ages [52]. The BrainEac.org gene-chip resource [52] [GEO:GSE60862] comprises ten post-mortem brain regions from 134 subjects representing 1231 samples (Additional file 1). Using the same ranking approach as applied to the ULSAM cohort, the median sum of the rank score was calculated for each anatomical brain region (Fig. 4a). As before, in healthy older individuals the ‘age’ signature was ‘switched on’ (yielding a greater ranking score) compared with younger subjects. Regulation of the healthy ageing gene score increased in a distinct manner across individual healthy brain regions with chronological age, especially in the hippocampus (p = 0.00000002), as well as other regions (putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions (all at least p < 0.002 by Holm adjusted Mann–Whitney test).Fig. 4


A novel multi-tissue RNA diagnostic of healthy ageing relates to cognitive health status.

Sood S, Gallagher IJ, Lunnon K, Rullman E, Keohane A, Crossland H, Phillips BE, Cederholm T, Jensen T, van Loon LJ, Lannfelt L, Kraus WE, Atherton PJ, Howard R, Gustafsson T, Hodges A, Timmons JA - Genome Biol. (2015)

The healthy ageing RNA signature in healthy human brain tissue and blood of AD patients and controls. There was robust regulation of the healthy ageing RNA signature in human brain with healthy ageing and between control subjects and subjects with AD or MCI. a The healthy ageing RNA signature was studied across brain regions in healthy individuals using BrainEac.org gene-chip resource [GEO:GSE60862]. Ten brain regions from 134 subjects representing 1231 samples were individually ranked (see “Materials and methods”) and the median sum of the ranked scores calculated. Regulation of the healthy ageing genes differed across brain regions with age, as determined by a Kruskal Wallis Test (hippocampus p = 0.00000002, putamen p = 0.00000004, thalamus p = 0.00004, temporal cortex p = 0.0001, substantia nigra p = 0.0002, frontal cortex p = 0.001, occipital cortex p = 0.001, white matter p = 0.01, medulla p = 0.06 and cerebellar cortex p = 0.51). Post hoc Mann–Whitney test, with correction for multiple comparisons (Holm), confirmed a striking ‘increase’ of the healthy ageing score in the healthy older samples (hippocampus, putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions; at least p < 0.002). b The healthy ageing RNA signature was studied in blood samples from two independently processed case–control studies of AD. In cohort 1 the control median gene score was greater (p = 0.004) than AD samples and greater (p = 0.00005) than that of the MCI samples (Wilcoxon rank sum test). In cohort 2 the median gene score of control samples was greater than that of AD samples (p = 0.009) and that of MCI samples (p = 0.003). Data are median gene score and standard error
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Fig4: The healthy ageing RNA signature in healthy human brain tissue and blood of AD patients and controls. There was robust regulation of the healthy ageing RNA signature in human brain with healthy ageing and between control subjects and subjects with AD or MCI. a The healthy ageing RNA signature was studied across brain regions in healthy individuals using BrainEac.org gene-chip resource [GEO:GSE60862]. Ten brain regions from 134 subjects representing 1231 samples were individually ranked (see “Materials and methods”) and the median sum of the ranked scores calculated. Regulation of the healthy ageing genes differed across brain regions with age, as determined by a Kruskal Wallis Test (hippocampus p = 0.00000002, putamen p = 0.00000004, thalamus p = 0.00004, temporal cortex p = 0.0001, substantia nigra p = 0.0002, frontal cortex p = 0.001, occipital cortex p = 0.001, white matter p = 0.01, medulla p = 0.06 and cerebellar cortex p = 0.51). Post hoc Mann–Whitney test, with correction for multiple comparisons (Holm), confirmed a striking ‘increase’ of the healthy ageing score in the healthy older samples (hippocampus, putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions; at least p < 0.002). b The healthy ageing RNA signature was studied in blood samples from two independently processed case–control studies of AD. In cohort 1 the control median gene score was greater (p = 0.004) than AD samples and greater (p = 0.00005) than that of the MCI samples (Wilcoxon rank sum test). In cohort 2 the median gene score of control samples was greater than that of AD samples (p = 0.009) and that of MCI samples (p = 0.003). Data are median gene score and standard error
Mentions: Neurocognitive pathology (e.g., AD) becomes more pronounced with age and is often apparent in individuals who are otherwise healthy. Our analysis of the relationship between lifestyle factors and the healthy ageing gene score in the ULSAM cohort suggested that the gene score was robust to confounding effects of lifestyle disease. We next examined whether the healthy ageing gene score (median rank sum of the 150 RNA markers) was selectively useful in relation to identifying neurocognitive disease over lifestyle disease. To support this analysis, we utilized a large publically available gene-chip data set derived from healthy human brain samples of various ages [52]. The BrainEac.org gene-chip resource [52] [GEO:GSE60862] comprises ten post-mortem brain regions from 134 subjects representing 1231 samples (Additional file 1). Using the same ranking approach as applied to the ULSAM cohort, the median sum of the rank score was calculated for each anatomical brain region (Fig. 4a). As before, in healthy older individuals the ‘age’ signature was ‘switched on’ (yielding a greater ranking score) compared with younger subjects. Regulation of the healthy ageing gene score increased in a distinct manner across individual healthy brain regions with chronological age, especially in the hippocampus (p = 0.00000002), as well as other regions (putamen, thalamus, substantia nigra, and the occipital, frontal, and temporal cortex regions (all at least p < 0.002 by Holm adjusted Mann–Whitney test).Fig. 4

Bottom Line: Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity.We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample.This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.

View Article: PubMed Central - PubMed

Affiliation: XRGenomics Ltd, London, UK.

ABSTRACT

Background: Diagnostics of the human ageing process may help predict future healthcare needs or guide preventative measures for tackling diseases of older age. We take a transcriptomics approach to build the first reproducible multi-tissue RNA expression signature by gene-chip profiling tissue from sedentary normal subjects who reached 65 years of age in good health.

Results: One hundred and fifty probe-sets form an accurate classifier of young versus older muscle tissue and this healthy ageing RNA classifier performed consistently in independent cohorts of human muscle, skin and brain tissue (n = 594, AUC = 0.83-0.96) and thus represents a biomarker for biological age. Using the Uppsala Longitudinal Study of Adult Men birth-cohort (n = 108) we demonstrate that the RNA classifier is insensitive to confounding lifestyle biomarkers, while greater gene score at age 70 years is independently associated with better renal function at age 82 years and longevity. The gene score is 'up-regulated' in healthy human hippocampus with age, and when applied to blood RNA profiles from two large independent age-matched dementia case-control data sets (n = 717) the healthy controls have significantly greater gene scores than those with cognitive impairment. Alone, or when combined with our previously described prototype Alzheimer disease (AD) RNA 'disease signature', the healthy ageing RNA classifier is diagnostic for AD.

Conclusions: We identify a novel and statistically robust multi-tissue RNA signature of human healthy ageing that can act as a diagnostic of future health, using only a peripheral blood sample. This RNA signature has great potential to assist research aimed at finding treatments for and/or management of AD and other ageing-related conditions.

No MeSH data available.


Related in: MedlinePlus