"Analysis of lifespan across Diversity Outbred mouse studies identifies multiple longevity-associated loci"
https://www.biorxiv.org/content/10.1101/2024.11.20.624531v3

| **B4galt6** | Encodes a β‑1,4‑galactosyltransferase that builds glycosaminoglycan chains, influencing extracellular‑matrix integrity and tissue‑repair pathways that decline with age. |
| **Ttr** (transthyretin) | Transports thyroid hormone and retinol; altered TTR levels or amyloid‑forming variants are linked to neurodegeneration and reduced lifespan in several model organisms. |
| **Trappc8** | Component of the TRAPP III tethering complex that regulates autophagosome formation, a process whose efficiency is critical for cellular homeostasis during aging. |
| **Rnf125** | E3 ubiquitin ligase that targets signaling adapters for degradation, modulating immune activation and proteostasis – both key determinants of age‑related inflammation. |
| **Rnf138** | Nuclear E3 ligase that ubiquitylates DNA‑damage response factors, helping maintain genomic stability, a hallmark of healthy aging. |
| **Mep1b** | Secreted metalloprotease that remodels the extracellular matrix and clears misfolded proteins, activities that decline with age and contribute to tissue stiffening. |
| **Garem1** | Poorly characterized protein with predicted guanine‑exchange activity; emerging data suggest it may influence signaling cascades that affect metabolic stress resistance. |
| **Klhl14** (Kelch‑like 14) | Substrate‑recruiting adaptor for Cullin‑3 ubiquitin ligase complexes, implicated in turnover of metabolic enzymes and thus in maintaining cellular energy balance with age. |
| **Ccdc178** | Coiled‑coil domain protein that interacts with mitochondrial dynamics regulators, potentially affecting mitochondrial quality control during aging. |
| **Axl3** | Putative membrane receptor related to the TAM family; its signaling can modulate inflammation and phagocytic clearance, processes that become dysregulated in old organisms. |
| **Susd6 / DRAGO** | Secreted protein induced by DNA‑damage stress; may act as a systemic alarm factor that coordinates repair and stress‑response pathways that protect longevity. |
| **Rgs6** (Rsg6) | Regulates G‑protein‑coupled‑signal termination in neurons and the heart, influencing catecholamine signaling and cardiovascular resilience in ageing. |
| **Rbfox1** | RNA‑binding splicing factor that controls alternative exon usage of metabolic and synaptic genes, thereby preserving neuronal function and metabolic homeostasis with age. |
| **Tmm114** | Predicted transmembrane protein of unknown function; orthologs are up‑regulated in long‑lived worms, hinting at a role in membrane‑associated stress resistance. |
| **Mettl22** | RNA methyltransferase that installs N6‑methyladenosine marks, modulating mRNA stability of stress‑response transcripts that influence lifespan. |
| **Tmem186** | Small integral‑membrane protein implicated in calcium handling; proper calcium homeostasis is critical for muscle and neuronal longevity. |
| **Pmm2** | Phosphomannomutase required for N‑glycosylation; defects cause congenital disorders, while efficient glycosylation supports protein folding and reduces age‑related proteotoxicity. |
| **Abat** | Enzyme that catabolizes GABA; altered GABA turnover affects neurotransmission and has been linked to age‑dependent cognitive decline. |
| **Carhsp1** | Calcium‑responsive transcription factor that regulates expression of stress‑protective genes, contributing to cellular resilience in aging tissues. |
| **Usp7** | Deubiquitinase that stabilizes p53, PTEN and other tumor‑suppressor proteins, thereby enhancing DNA‑repair capacity and limiting age‑associated malignancy. |

prompt> Look at each of the genes identified above and rewrite this whole section to be more accurate as to the function or purpose of each of the enzymes or proteins and with regards to its role in longevity. Be careful and try not to speculate too much, and if you don't know something, then don't include it. However, each gene that was referenced originally should still be referenced in the final output.

--- Command output (model: openrouter/anthropic/claude-opus-4.5) ---
| **B4galt6** | Encodes β-1,4-galactosyltransferase 6, which catalyzes the transfer of galactose to glucosylceramide to synthesize lactosylceramide, a precursor for more complex glycosphingolipids. These lipids are components of cell membranes and participate in cell signaling. The enzyme's specific connection to aging remains poorly characterized. |
| **Ttr** (transthyretin) | A homotetrameric plasma protein synthesized primarily in the liver and choroid plexus that transports thyroxine (T4) and retinol (via retinol-binding protein). Misfolding of TTR causes hereditary and wild-type transthyretin amyloidosis, a systemic disease with cardiac involvement that increases in prevalence with age. |
| **Trappc8** | A subunit of the TRAPP III complex involved in membrane trafficking, particularly in regulating the transition from ER-to-Golgi transport and autophagosome formation. Autophagy is a conserved process important for cellular quality control, and its decline has been associated with aging in multiple organisms. |
| **Rnf125** | An E3 ubiquitin ligase that ubiquitinates RIG-I and other signaling molecules involved in antiviral innate immune responses. By promoting degradation of these factors, RNF125 negatively regulates type I interferon production. Its direct role in aging has not been well established. |
| **Rnf138** | A RING-type E3 ubiquitin ligase that participates in DNA double-strand break repair by promoting end resection during homologous recombination. It ubiquitinates Ku80, facilitating its removal from DNA ends. Maintenance of DNA repair capacity is recognized as important for genome stability during aging. |
| **Mep1b** | Encodes the beta subunit of meprin, a zinc metalloprotease expressed in intestinal and kidney epithelial cells. Meprin cleaves various substrates including extracellular matrix proteins, cytokines, and bioactive peptides. Its specific role in aging-related processes is not well defined. |
| **Garem1** | Encodes GRB2-associated and regulator of MAPK protein 1, which functions as a scaffold protein in receptor tyrosine kinase signaling, particularly downstream of EGF receptor activation. It enhances ERK signaling. Its relationship to aging is not well characterized in the literature. |
| **Klhl14** (Kelch-like 14) | A BTB-Kelch family protein predicted to function as a substrate adaptor for Cullin-3 ubiquitin ligase complexes. The specific substrates targeted by KLHL14 and its physiological functions remain poorly characterized, including any potential role in aging. |
| **Ccdc178** | Encodes a coiled-coil domain-containing protein. Limited functional characterization exists for this gene in the published literature. Any role in mitochondrial function or aging remains speculative. |
| **Axl** | A receptor tyrosine kinase of the TAM family (TYRO3, AXL, MER). AXL is activated by its ligand GAS6 and regulates processes including cell survival, efferocytosis (clearance of apoptotic cells), and dampening of innate immune responses. Impaired efferocytosis has been implicated in age-related pathologies. |
| **Susd6** | Encodes sushi domain-containing protein 6. This gene is not well characterized functionally, and claims about DNA damage induction or systemic signaling roles require verification against primary literature. |
| **Rgs6** | A regulator of G-protein signaling that accelerates GTP hydrolysis by Gαi/o subunits, thereby terminating G-protein-coupled receptor signaling. RGS6 is expressed in heart and brain and has been implicated in cardiac pacemaker regulation and modulation of muscarinic and dopaminergic signaling. |
| **Rbfox1** | An RNA-binding protein that regulates alternative splicing by binding to (U)GCAUG elements in pre-mRNA. RBFOX1 controls splicing of numerous transcripts important for neuronal and muscle function. Variants in RBFOX1 have been associated with neurological and neurodevelopmental conditions. |
| **Tmem114** | Encodes a predicted transmembrane protein. Functional characterization of this gene in mammalian systems is limited, and assertions about orthologs in longevity studies require specific citations. |
| **Mettl22** | Encodes a methyltransferase that has been shown to methylate the eukaryotic chaperone protein KIN/Kin17 on lysine residues, rather than functioning as an RNA m6A methyltransferase. Its role in aging is not established. |
| **Tmem186** | Encodes a small transmembrane protein of the mitochondrial inner membrane, recently identified as a component of the mitochondrial respiratory chain assembly machinery. Its specific role in calcium handling or aging requires further evidence. |
| **Pmm2** | Phosphomannomutase 2 converts mannose-6-phosphate to mannose-1-phosphate, a step required for synthesis of GDP-mannose used in N-linked glycosylation. Mutations in PMM2 cause PMM2-CDG (congenital disorder of glycosylation), the most common CDG subtype, causing multisystem disease. |
| **Abat** | Encodes 4-aminobutyrate aminotransferase, a mitochondrial enzyme that catalyzes the catabolism of gamma-aminobutyric acid (GABA) to succinic semialdehyde. ABAT deficiency causes a rare metabolic disorder with neurological manifestations. GABA metabolism changes during brain aging, though ABAT's specific role in age-related cognitive decline requires further study. |
| **Carhsp1** | Encodes calcium-regulated heat-stable protein 1, a small protein that binds to the 3' UTR of TNF-alpha mRNA and regulates its stability. CARHSP1 may influence inflammatory cytokine expression. Characterization as a transcription factor appears inaccurate based on current literature. |
| **Usp7** | A deubiquitinating enzyme (also called HAUSP) that removes ubiquitin from multiple substrates including p53, MDM2, PTEN, and FOXO transcription factors. By stabilizing both p53 and its negative regulator MDM2, USP7 plays a complex role in regulating the p53 pathway, DNA damage responses, and tumor suppression. |