C/EBPβ as a Longevity Gene

Few longevity-associated genes are demonstrated to work in both directions in animal studies, either enhancing or reducing life span depending on whether there is more or less of the protein produced. Klotho is one of the better studied examples. Here researchers note the evidence for C/EBPβ to be another such longevity gene, wherein more C/EBPβ leads to a shorter life span. Removing C/EBPβ completely is not a good idea, since it is essential for a variety of important aspects of our biology, such as the function of macrophage cells. Reducing it, however, extends life.

What can one do with this information? In the case of klotho, something approaching two decades of study has led to inroads toward an understanding of the mechanisms of importance, and a preclinical development program aimed at the use recombinant klotho protein as a therapy. There is clearly a long way to go yet. Like klotho, C/EBPβ influences a great many cellular mechanisms, and it will take a great deal of time and effort to even begin to distinguish what is important from what is a distraction. The wheels turn slowly when it comes to the effective manipulation of metabolism as a basis for treatments to slow aging.

C/EBPβ/AEP pathway dictates both Alzheimer's disease and longevity

C/EBPβ is a transcription factor that promotes Alzheimer's disease pathologies via activating asparagine endopeptidase (AEP) in response to amyloid-β and inflammatory cytokines.

To explore C/EBPβ's role in aged nerve cells, researchers generated a mouse model that selectively overexpresses C/EBPβ in the brain to mimic aged animals. Researchers found that the mice's life span was shortened in a gene dose-dependent manner. Usually, normal life expectancy for a mouse is around 24-28 months. However, the life span for a mouse carrying one copy of overexpressed C/EBPβ is around 12-18 months and 5-9 months for mice carrying two copies. By contrast, deleting one copy of the C/EBPβ gene increases the life span with the most long-lived mice living more than 30 months.

The C/EBPβ gene is elevated in human brains during aging. It peaks in individuals 60 to 84 years old and declines in those more than 85 years old. Long-lived individuals usually show less expression of AEP genes in nerve cells, whereas short-lived individuals show greater AEP gene expression.

In worms, neural excitation increases with age and inhibition of excitation increases longevity. The scientists found that high levels of C/EBPβ or AEP in nerve cells shorten the worm's life span, whereas such gene expression in muscles has no effect on longevity. Similar to mice, deletion of these genes in worms increases the life span. Remarkably, inhibition of AEP using a drug increases the life expectancy of worms.

Life span regulation by insulin-like metabolic control is analogous to mammalian longevity enhancement induced by caloric restriction, suggesting a general link between metabolism and longevity. The researchers found that C/EBPβ/AEP signaling was inversely correlated with insulin signaling in the human brain. With the lowest insulin signaling in humans in their seventies and eighties, C/EBPβ/AEP activity peaks. However, in humans with extended longevity, C/EBPβ/AEP activity declines, while insulin signaling climbs in the brain.

Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression

The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPβ, an Aβ and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPβ transgenic mice. C/EBPβ selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction.

Overexpression of CEBP-2 (ortholog of C/EBPβ) or LGMN-1 (orthology of AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPβ and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPβ/AEP pathway.

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