Advantages of using a combinatorial approach, employing both C. elegans and mammalian systems, in aging research. C. elegans has various advantages as a model organism in aging research, e.g., genetic tractability for random mutagenesis and RNAi screen, a large brood size, and a relatively short wild-type lifespan of 2-3 weeks. Mammalian systems, such as mouse models, compensate the limitations of C. elegans because of their physiological similarity to humans, suitability as age-associated disease models (such as being models of Alzheimer’s disease and sarcopenia), and amenability to organ-level approaches. By exploiting the advantages of these two complementary model systems, researchers can efficiently elucidate evolutionarily conserved aging mechanisms.|@|~(^,^)~|@|Schematic models for combinatorial C. elegans and mammalian system studies regarding the role of insulin/IGF-1 signaling, mTOR pathway, and sirtuins. (A) DAF-16/forkhead box O (FOXO) is activated by genetic inhibition of EFL-1/E2F1 while being inhibited by mutations in ercc-1/Ercc1. Activated DAF-16/FOXO delays aging by increasing target gene expression. (B) Reduced mechanistic target of rapamycin (mTOR) signaling by genetic inhibition or treatment with rapamycin activates adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) via downregulating RSKS-1/S6K1 and upregulates SKN-1/Nrf to induce protective genes, leading to longevity. (C) Kallistatin downregulates miR-34a leading to the activation of SIR-2.1/SIRT1 to delay aging. Increased nicotinamide adenine dinucleotide (NAD⁺) levels also delay aging through upregulation of SIR-2.1/SIRT1.|@|~(^,^)~|@|Combinatorial C. elegans and mammalian studies regarding the conserved aging regulation by dietary restriction, autophagy, mitochondria, and neuronal system. (A) Dietary restriction upregulates age-dependently downregulated mRNA processing and quality control by improving proper alternative splicing coupled with nonsense-mediated mRNA decay (NMD). Dietary restriction also upregulates DCR-1/Dicer and DRSH-1/Drosha, ribonucleases responsible for miRNA processing, thereby improving longevity-associated miRNA processing. Enhanced mRNA processing and quality control, and miRNA processing contribute to longevity and enhanced fitness in C. elegans and mammals. (B) Autophagy activation regulates aging in a context-dependent manner. HLH-30/TFEB and Krüppel-like transcription factor delay aging by enhancing autophagy. In contrast, genetic inhibition of serum/glucocorticoid-regulated kinase 1 (SGK-1/Sgk1) accelerates aging by activating autophagy. (C) Reduced mitochondrial respiration induces mitochondrial unfolded protein response (UPR^mt) and promotes longevity through activation of histone deacetylase HDA-1/HDAC, histone lysine demethylase JMJD-3.1/JMJD3, and histone acetyltransferase CBP-1/CBP/p300. Increased levels of NAD⁺ promote longevity and ameliorate age-associated disease models via enhancing mitophagy and UPR^mt. (D) Levels of SPR-3/4/REST positively correlate with lifespan in C. elegans, mice, and humans. SPR-3/4/REST downregulates neural activity and synaptic function to promote longevity. Increased NAD⁺ and SPR-3/4/REST levels ameliorate the toxicity caused by amyloid β in C. elegans and mice.

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