Centenarians Exhibit a Higher Expression of Metallothioneins in Astrocytes
A considerable amount of effort has gone into assessing the biochemical differences between old people and extremely old people, in search of protective mechanisms that might be used as a basis for therapies to modestly slow the pace of aging. This may not be the best approach from the point of view of size of effect achieved at the end of the day, as centenarians are still meaningfully impacted by aging, their physiology far removed from that of a young individual, but it is an approach well suited to the present environment of low cost omics technologies. Everything that can be measured attracts attention, and the cheaper the measure is to enact, the more that researchers will use it.
Previous studies of the aging human brain have shown dynamic gene expression changes that distinguish young adults from the aging population. Independent transcriptome analyses showed shifts in the expression of different glial-specific genes and indicated that inflammatory or immune-responsive genes are upregulated during aging in most brain regions, increasing the vulnerability of the brain to cognitive aging. Moreover, a recent transcriptomic study performed in frontal cortex samples of individuals organized in two different groups according to their age (≤80 vs. ≥85 years) showed that the ≥85 years group of age was associated with a distinct transcriptome signature in the cerebral cortex and revealed a protective mechanism of aging and longevity mediated by neural circuit activity.
Centenarians are a group that exhibits extreme longevity, which is commonly accompanied by better quality of life, physical independence, and cognitive function compared to older individuals dying in 70s or 80s. Omic approaches in blood samples from centenarians revealed that the transcriptome and the expression pattern of noncoding RNAs are more similar to young individuals than septuagenarians. Different studies have also described that centenarians present a reduced number of cases with neurodegenerative diseases, in some cases avoid dementia. Consistent with these ideas, our recent study characterizing Basque centenarians identified that they showed better biological profiles in blood analysis, required fewer use of medical resources, and developed fewer diseases including from the nervous system compared with non-centenarians.
We performed transcriptomic studies in hippocampus samples from individuals of different ages (centenarians, here meaning those ≥97 years of age, old, and young) and identified a differential gene expression pattern in centenarians compared to the other two groups. In particular, several isoforms of metallothioneins (MTs) were highly expressed in centenarians. Moreover, we identified that MTs were mainly expressed in astrocytes. Functional studies in human primary astrocytes revealed that MT1 and MT3 are necessary for their homeostasis maintenance. The concentration of zinc in the brain surpasses that of the body by 10-fold and it is essential for normal functioning. There is a link between zinc levels in the brain and cognitive function, and the decline in cognitive performance observed during aging has been linked to the dysregulation of zinc homeostasis. MTs, zinc transporters family (ZnTs), presenilins, and zinc-regulated and iron-regulated proteins (ZIPs) are responsible for the homeostasis of zinc in the brain. Overall, these results indicate that the expression of MTs specifically in astrocytes is a mechanism for protection during aging.