Pasam Elizabeth S, Madamanchi Kishore, Melkani Girish C
Department of Pathology, Division of Molecular and Cellular Pathology, Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
UAB Nathan Shock Center, Birmingham, AL, 35294, USA.
Biogerontology. 2025 Aug 19;26(5):165. doi: 10.1007/s10522-025-10306-y.
Aging disrupts physiological and behavioral homeostasis, largely driven by one-carbon metabolism, mitochondrial, and metabolic imbalance. To elucidate the roles of conserved metabolic and mitochondrial genes in age-related decline, we employed genetic manipulations in vivo using Drosophila melanogaster models, in a cell-autonomous and non-cell-autonomous manner. By using panneuronal and indirect flight muscle (IFM) specific drivers, we assessed the impact of gene knockdown (KD) or overexpression (OE) on sleep-circadian rhythms, locomotion, and lipid metabolism in a cell-autonomous and non-cell-autonomous manner to address bidirectional neuro-muscle communications. KD of genes such as SdhD and Gnmt leads to a decrease in flight performance, especially in 6 weeks with both drivers. Panneuronal knockdown of genes did not impact the locomotory performance. Whereas knockdown of mAcon1, LSD2, Ampkα, Ald, and Adsl genes showed reduced flight performance, with only IFM-specific driver emphasizing the cell-autonomous role of metabolic genes. Panneuronal KD of Ald, GlyP, mAcon1, and Gnmt genes showed increased total sleep, reduced activity, while Adsl and Ogdh knockdown led to sleep fragmentation, in a mid-age suggests cell-autonomous impact. Functional analysis of AMPK signaling via overexpression and knockdown of Ampkα, as well as expression of the mutant overexpression SNF1A and its kinase-dead mutant, revealed kinase-dependent, age- and tissue-specific modulation of sleep and activity rhythms. Lipid analysis showed that panneuronal overexpression of Ampkα altered lipid droplet number and size in the brain, indicating disrupted lipid homeostasis during aging. These findings on various genes provide us with an understanding of their diverse effects on sleep-activity rhythms, locomotor effects, and communication in cell and non-cell-autonomous roles. Our study emphasizes Ampkα as a central regulator of behavioral and metabolic aging, linking neuronal energy sensing, motor function, and lipid dynamics, and offers mechanistic insights into tissue-specific metabolic regulation with potential relevance for interventions targeting age-related decline and neurodegeneration.
衰老会破坏生理和行为的稳态，这在很大程度上是由一碳代谢、线粒体和代谢失衡所驱动的。为了阐明保守的代谢和线粒体基因在与年龄相关的衰退中的作用，我们以细胞自主和非细胞自主的方式，在果蝇模型中进行了体内基因操作。通过使用全神经元和间接飞行肌（IFM）特异性驱动因子，我们以细胞自主和非细胞自主的方式评估了基因敲低（KD）或过表达（OE）对睡眠-昼夜节律、运动和脂质代谢的影响，以解决双向神经-肌肉通讯问题。SdhD和Gnmt等基因的敲低会导致飞行性能下降，尤其是在使用两种驱动因子的6周龄果蝇中。全神经元基因敲低不会影响运动性能。而mAcon1、LSD2、Ampkα、Ald和Adsl基因的敲低则显示飞行性能下降，只有IFM特异性驱动因子强调了代谢基因的细胞自主作用。Ald、GlyP、mAcon1和Gnmt基因的全神经元敲低显示总睡眠时间增加、活动减少，而Adsl和Ogdh敲低则导致睡眠碎片化，这表明在中年时存在细胞自主影响。通过过表达和敲低Ampkα对AMPK信号进行功能分析，以及突变体过表达SNF1A及其激酶失活突变体的表达，揭示了激酶依赖性、年龄和组织特异性对睡眠和活动节律的调节。脂质分析表明，Ampkα的全神经元过表达改变了大脑中脂滴的数量和大小，表明衰老过程中脂质稳态受到破坏。这些关于各种基因的发现让我们了解了它们对睡眠-活动节律、运动效应以及细胞和非细胞自主作用中的通讯的不同影响。我们的研究强调Ampkα是行为和代谢衰老的核心调节因子，它将神经元能量感知、运动功能和脂质动态联系起来，并为组织特异性代谢调节提供了机制性见解，这可能与针对年龄相关衰退和神经退行性变的干预措施相关。
