Recently, Phenomics published online the collaborative research work of Yu Wei's group at Fudan University and Han Jingdong's research group at Peking University, "Immunosuppression induced by brain-specific HDAC6 knockdown improves aging performance in Drosophila melanogaster". This work, which uses Drosophila as a model organism, combined with senescent phenotype group studies, found that specific knocking down histone deacetylatase HDAC6 in the brains of Drosophila can inhibit the expression of aging-related inflammatory genes and achieve anti-aging.
Histone deacetylatase HDAC6 is involved in the development of a variety of aging-related diseases. In the study, using Drosophila as a model organism, it was found that knocking down HDAC6 in the brains of Drosophila led to significant changes in the transcriptome, particularly a significant downregulation of transcriptional levels of inflammatory responses and innate immune-related genes. Behavioral experiments have found that systemic knocking down HDAC6 in drosophila can prolong the lifespan of drosophila and improve the crawling ability of drosophila. Moreover, specific knockdown of HDAC6 in the brain can further prolong the lifespan of drosophila and improve the motor ability of drosophila compared with systemic knockdown. Interestingly, specifically knocking down HDAC6 in the brains of senescent flies also significantly prolongs the lifespan of flies. The study found that HDAC6 exerts an important anti-aging effect in nerves by inhibiting the expression of immuno-inflammatory-related genes, which provides a potential target for delaying aging.
Research background
Aging is an important biological process that occurs in living organisms, accompanied by various physiological and functional changes in various systems, tissues and organs, such as neurodegeneration, immune dysfunction and decline in motor ability. HDAC6 is a member of the DEACECIIb class mainly located in the cytoplasm, which contains two tandem catalytic domains and the C-terminal zinc finger domain, so that HDAC6 can not only play the function of deacetylase, deacetylating modification of histones or non-histones; it can also regulate biological processes such as autophagy and immune response. In the early stages, the researchers found that compared with other members of the HDAC family, only the knockout induction of HDAC6 underwent an overall change, and the effect was consistent with the effect of the HDAC inhibitor SAHA. However, the mechanisms by which HDAC6 is directly involved in regulating body health and longevity are not fully understood. The study specifically knocked down HDAC6 throughout the body or brain, finding that this can induce inflammatory immunosuppression, which in turn prolongs the lifespan of drosophila. Therefore, the researchers have tentatively determined that HDAC6 is directly involved in the anti-aging effects by inducing immunosuppression.
Research results
01 Knocking down the HDAC6 gene in Drosophila brains inhibits transcription of immune-related genes
Firstly, in order to detect the targets of HDAC6 action in the aging process, the researchers collected the heads of elderly Drosophila for transcriptome analysis, and explored the gene transcriptional changes in the aging process of control flies and systemic knockdown HDAC6 flies, respectively. In the control Drosophila group, genes that are upregulated by transcription are mostly associated with innate immunity and inflammatory response function as they age. This result is consistent with the view that "the strength of the inflammatory response in the body is a key factor affecting the aging and life expectancy of the body", and with age, the body will have a continuous intensification of pro-inflammatory response, inflammation homeostasis imbalance and other phenomena. Genes that are downregulated by transcription are mostly associated with mitochondrial function and chitin metabolism (Figure 1a). In the Drosophila group that knocked down HDAC6, the researchers found that knocking down HDAC6 significantly downregulated transcriptional expression of innate immune and inflammatory response genes that rise with aging in normal Drosophila, thereby reducing the inflammatory response in drosophila's head (Figures 1a-1b), which is the same as some current studies of HDAC6 inhibitors. By GO enrichment analysis, the genes in control group Drosophila and Knockdown HDAC6 flies decreased with senescence, but most of the inflammation-related genes that rose with senescence expression in control Drosophila were expressed in HDAC6 knockdown flies (Figures 1c-1d). Therefore, the researchers believe that HDAC6 can positively regulate immune-related genes during drosophila aging, and knocking down HDAC6 can significantly inhibit the over-activation of innate immune and inflammatory response genes.
Figure 1
02 Specifically knocking down HDAC6 in the brain can improve the health and longevity of Drosophila
To explore whether knocking down HDAC6 in Drosophila had an effect on Drosophila's motor ability and longevity, the researchers used systemically expressed Da-gal4 to knock down HDAC6 in Drosophila. They found that knocking down HDAC6 does prolong the survival time of fruit flies (Figure 2a).
The tube climbing experiment is a classic measure of the athletic ability of fruit flies, after shaking all fruit flies to the bottom of the tube, record the crawling time it takes for the first 5 of each strain to climb to the 6 cm tick mark. The shorter the crawling function, the better the movement ability of the fruit flies. In this study, systemic knockdown of HDAC6 was found to significantly improve the motor ability of Fruit flies (Figure 2b).
Since HDAC6 plays an important role in neurological diseases, and HDAC6 inhibitors have a good effect in the treatment of neurological diseases, they further knock down HDAC6 specifically in drosophila brains with neurally specifically expressed Elav-gal4. The results showed that specific knocking down HDAC6 in drosophila brains also prolonged the lifespan of Drosophila and improved their motor capacity, which also confirmed the important role of knocking down HDAC6 in drosophila brains for anti-aging (Figures 2c-2d).
To further demonstrate that specific knockdown of HDAC6 in the brain can also play a role in older Drosophila, the researchers used a chemically induced Gal80-DD system to specifically knock down HDAC6 in the brains of older Drosophila and to test whether lifespan can be extended (Figure 2e). The researchers crossed UES-HDAC6Ri flies with Elav-gal4, Gal80-DD flies and collected offspring flies in two groups for lifespan experiments. In the first 25 days, both groups of flies were raised with food with 0.5 mM TMP added, at which point HDAC6 was not knocked down; on the 25th day, one group of fruit flies was changed to a food feeding with DMSO and no TMP, thereby inducing knockdown hdAC6, while the other group of fruit flies continued to raise food with TMP added. Experiments have shown that specific knocking down HDAC6 in the brains of older drosophila can significantly prolong the lifespan of drosophila. Therefore, the researchers concluded that inhibiting HDAC6 in the brain of Drosophila can exert anti-aging effects in Drosophila.
More interestingly, when they compared the lifespan and motor capacity of brain-specific knockdown HDAC6 with systemic knockdown hdAC6 flies, they found that the brain-specific knockdown HDAC6 flies survived longer and were more athletic (Figures 2f-2g). This suggests that the brain is an important tissue for the anti-aging effects of HDAC6.
Figure 2
Conclusions of the study
This study found that HDAC6 may be used as a direct target for regulating healthy lifespan, especially in neural tissues such as the brain, by inhibiting the expression of inflammatory genes and exerting anti-aging effects. Knocking down HDAC6 can reduce the immune and inflammatory response in the brain, improve motor performance, and prolong the lifespan of fruit flies.
However, further in-depth research is needed as to whether HDAC6 regulates lifespan through specific target genes in immune and inflammatory signaling pathways, and whether it plays a similar role in other tissues. Consistent with this, recent work in the Dang Weiwei Laboratory of Baylor College of Medicine in the United States has shown that the knockdown of yeast HDA congeners in nematodes and fruit flies also delays the rate of physical decline associated with aging and prolongs lifespan. These studies suggest that inhibiting HDAC6 can promote health and longevity in different species, suggesting that inhibition of HDAC6 may be a promising strategy for intervening in aging.
Abstract
Yu Wei, a researcher at the School of Life Sciences of Fudan University and Professor Han Jingdong of the Institute of Frontier Interdisciplinarity of Peking University, is the corresponding author of the paper, and graduate students Zhao Yingying and Xuan Hongwen are co-first authors. The research was supported by the National Natural Science Foundation of China (31771545, 92049301, 31821002, 91329302 and 31210103916); the Ministry of Science and Technology Project (2015CB964803, 2016YFE0108700 and 2016YFA0500600); and the Max Planck Scholarship.
Source: Human Phenotypic Group Program