Abstract
The Leiden Longevity Study consists of families that express extended survival across generations, decreased morbidity in middle-age, and beneficial metabolic profiles. To identify which pathways drive this complex phenotype of familial longevity and healthy aging, we performed a genome-wide gene expression study within this cohort to screen for mRNAs whose expression changes with age and associates with longevity. We first compared gene expression profiles from whole blood samples between 50 nonagenarians and 50 middle-aged controls, resulting in identification of 2,953 probes that associated with age. Next, we determined which of these probes associated with longevity by comparing the offspring of the nonagenarians (50 subjects) and the middle-aged controls. The expression of 360 probes was found to change differentially with age in members of the long-lived families. In a RT-qPCR replication experiment utilizing 312 controls, 332 offspring and 79 nonagenarians, we confirmed a nonagenarian specific expression profile for 21 genes out of 25 tested. Since only some of the offspring will have inherited the beneficial longevity profile from their long-lived parents, the contrast between offspring and controls is expected to be weak. Despite this dilution of the longevity effects, reduced expression levels of two genes, ASF1A and IL7R, involved in maintenance of chromatin structure and the immune system, associated with familial longevity already in middle-age. The size of this association increased when controls were compared to a subfraction of the offspring that had the highest probability to age healthily and become long-lived according to beneficial metabolic parameters. In conclusion, an “aging-signature” formed of 21 genes was identified, of which reduced expression of ASF1A and IL7R marked familial longevity already in middle-age. This indicates that expression changes of genes involved in metabolism, epigenetic control and immune function occur as a function of age, and some of these, like ASF1A and IL7R, represent early features of familial longevity and healthy ageing.
Highlights
Nonagenarians and centenarians delay or escape age-related diseases [1], their first degree family members have a life-long survival advantage [2,3] and their middle-aged offspring have a decreased prevalence of and mortality from coronary heart disease, type 2 diabetes, and cancer [4,5]
Whole genome microarrays and analysis design Gene expression profiles were generated from 150 whole blood total RNA samples collected from 50 families belonging to the Leiden Longevity Study (LLS)
The first analysis focused on the comparison between the long-lived nonagenarians and the population controls. Using this design we aimed to find genes whose expression changed with increasing age and among these, those that were differentially expressed in long-lived families
Summary
Nonagenarians and centenarians delay or escape age-related diseases [1], their first degree family members have a life-long survival advantage [2,3] and their middle-aged offspring have a decreased prevalence of and mortality from coronary heart disease, type 2 diabetes, and cancer [4,5]. The offspring of long-lived individuals have beneficial physiological characteristics for lipid and lipoprotein particle profiles [6,7], glucose metabolism and insulin sensitivity [8,9]. They do not differ from controls with respect to body mass index, serum IGF-1 levels, height and lifestyle factors such as physical activity levels and smoking behavior [10,11]. The expression of some genes were found to change with age and to reflect the biological function of the source organs [18,19] These studies have demonstrated that gene expression levels are markers of chronological age and of tissue function. These studies cannot discriminate between genes showing expression changes in mid-life that may contribute to the aging process, from those showing expression changes later in life as a consequence of the aging process
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