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diff --git a/genetic-modifications.mdwn b/genetic-modifications.mdwn index 88b284c..23b903a 100644 --- a/genetic-modifications.mdwn +++ b/genetic-modifications.mdwn @@ -1158,6 +1158,142 @@ skin aging: "<a href="http://www.jdsjournal.com/article/S0923-1811(16)31087-8/ab CBP2/TAFI (carboxypeptidase B2) SNP -438A/A (rs2146881) from <a href="https://www.sciencedirect.com/science/article/abs/pii/S0021915005000481?via%3Dihub#preview-section-snippets">Reiner 2015</a> "was found to have extended healthy lifespan by 1.1 years (and overall lifespan by 0.9 years) in men (2224 subjects)." (<a href="https://www.reddit.com/r/Biohackers/comments/108ncxs/cbp2_438ga_as_a_target_for_extending_human/">reddit</a>) +## Mammals (mostly mice) + +GH/IGF signaling & nutrient sensing: + +* IGF-1 receptor haploinsufficiency (Igf1r+/-), longevity effect especially strong in female [PubMed](https://pubmed.ncbi.nlm.nih.gov/12483226/) +* consider other insulin/IGF receptor mutations +* growth hormone receptor knockout (GHRKO) ("Laron" model) [Wiley Online Library](https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1474-9726.2009.00520.x?utm_source=chatgpt.com) +* IRS1 knockout (Irs1-/-), sex-biased though [PubMed](https://pubmed.ncbi.nlm.nih.gov/17928362/?utm_source=chatgpt.com) +* S6K1 knockout (S6k1-/-; mTOR axis), especially strong effect in females [PubMed](https://pubmed.ncbi.nlm.nih.gov/19797661/) +* AKT1 haploinsufficiency (Akt1+/-), longer lifespan with metabolic shifts related to mTOR and autophagy [PLOS](https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0069178&utm_source=chatgpt.com) +* FGF21 transgenic overexpression, lifespan extension via GH/IGF modulation [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3466591/?utm_source=chatgpt.com), or [adipocyte-specific FGF21](https://www.cell.com/cell-metabolism/abstract/S1550-4131%2825%2900267-0?utm_source=chatgpt.com) + +sirtuins & stress response: + +* SIRT6 overexpression (whole-body), also shown to reduce frailty in B6 mice. [Nature](https://www.nature.com/articles/nature10815?utm_source=chatgpt.com) +* brain-specific SIRT1 overexpression (BRASTO mice), increase median and max lifespans, via hypothalamic mechanism [PubMed](https://pubmed.ncbi.nlm.nih.gov/24011076/) + +oxidative stress & mitochondria: + +* Mitochondrial catalase transgenic (MCAT), increase of median and max lifespan, downregulates oxidative damage. [PubMed](https://pubmed.ncbi.nlm.nih.gov/15879174/) + +KLOTHO: + +* KLOTHO overexpression (KlTg): improved lifespan, endocrine effects on insulin/IGF signaling. [PubMed](https://pubmed.ncbi.nlm.nih.gov/16123266/?utm_source=chatgpt.com) + +Myc & growth control: + +* Reduced Myc expression (haploinsufficiency): longer healthy lifespan with broad protection [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3494070/?utm_source=chatgpt.com) + +p66Shc (ROS signaling adaptor) knockout: unclear whether this has a positive effect or not [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4624921/?utm_source=chatgpt.com) + +senescent-cell clearance (genetic "senolysis"): + +* INK-ATTAC transgene (drug-inducible ablation of p16Ink4a+ cells) [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4845101/?utm_source=chatgpt.com) + +telomeres: + +* [Telomerase (TERT) overexpression](https://pubmed.ncbi.nlm.nih.gov/19013273/?utm_source=chatgpt.com): delayed aging and increased longevity without extra cancer in treated cohorts (AAV gene therapy of wildtype mice in this study) [PubMed](https://pubmed.ncbi.nlm.nih.gov/23066506/?utm_source=chatgpt.com) + +## Brain / hypothalamus (neuron-focused) + +* brain-specific SIRT1 overexpression (already mentioned) +* inhibiting hypothalamic IKKβ/NF-κB slows whole-body aging and extended lifespan, via central neuro-immune axis [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3756938/?utm_source=chatgpt.com) +* some sort of role played by hypothalamic neural stem/progenitor cells, where ablation accelerates aging, and transplantation or stem-cell exosomes slows aging and extends lifespan [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC5999038/?utm_source=chatgpt.com) + +## Adipose / endocrine adipokines + +* fat-specific insulin receptor knockout (FIRKO) produces a lean phenotype with increased lifespan via different adipose insulin signaling. [PubMed](https://pubmed.ncbi.nlm.nih.gov/12543978/?utm_source=chatgpt.com) +* adiponectin overexpression (ΔGly Tg): healthier aging with a median lifespan increase, knockout shortens lifespan. [eLife](https://elifesciences.org/articles/65108?utm_source=chatgpt.com) + +# Liver-driven endocrine signals + +* FGF21 transgenic (liver-secreted "starvation" hormone) [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3466591/?utm_source=chatgpt.com) + +## Vasculature / endothelium + +* endothelium-targeted Sirt7 gene therapy (ICAM2 promoter) [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7030934/?utm_source=chatgpt.com) +* counteracting age-related VEGF insufficiency (vascular rejuvenation) [PubMed](https://pubmed.ncbi.nlm.nih.gov/34326210/?utm_source=chatgpt.com) + +## Skeletal muscle (myokine/autophagy axis) + +* muscle-specific TFEB overexpression, causing improved muscle proteostasis and reduced brain neuroinflammation [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC10841857/?utm_source=chatgpt.com) + +## Heart (cardiomyocytes) + +* cardiac-specific catalase overexpression [PubMed](https://pubmed.ncbi.nlm.nih.gov/17201740/?utm_source=chatgpt.com) + +## Strategies for engineered negligible senescence + +Aubrey de Grey proposed "Strategies for Engineered Negligible Senescence" which includes the following: + +<https://sens.org/> + +[Strategies for Engineered Negligible Senescence](https://www.lifespan.io/our-research/intro-to-sens-research/?utm_source=chatgpt.com) is a repair-based approach to aging. It consists of seven categories of molecular and cellular damage that accumulate with age and proposes targeted adult interventions to keep their levels below the threshold that causes pathology. While SENS is primarily focused on adult aging, many of the concepts can be used to inform human germline genetic engineering for anti-aging. + +* cell loss (like from non-dividing cells) and atrophy requires replacement (RepleniSens) via tissue engineering and stem cell therapies to restore cell numbers and function. Stimulation or proliferation of resident progenitors to replace lost cells. +* death-resistant (senescent) cells must be removed (ApoptoSens) via targeted ablation such as through senolytic drugs or via immune/CAR-T approaches. p16-activated caspase, senolytic small molecule therapy (dasatinib, quercetin, navitoclax), immune-mediated clearance of senescent cells (CAR-NK cells, vaccination against senescent antigens). +* extracellular aggregates require immunoclearance (AmyloSENS): use vaccination/antibody therapies to tag and remove amyloids such as Aβ or transthyretin in tissue spaces. Active or passive immunization to tag aggregates for microglia/macrophage uptake. Use catalytic monoclonal antibodies or nanobodies that enhance proteolysis. Use engineered proteases like neprilysin or MMP variants. See [neprilysin overexpression](https://pmc.ncbi.nlm.nih.gov/articles/PMC2768427/?utm_source=chatgpt.com). Enhance endogenous clearance pathways. alagebrium (ALT-711) analogue expression during thymic negative selection. +* intracellular aggregates should be digested by better lysosomes (LysoSENS) by introducing novel lysosomal enzymes (like those sourced from microbes) to digest stubborn junk like oxidized cholesterol adducts and lipofuscin that materially clog lysosomes. Genomically encode modified enzymes with better trafficking and activity, like bacterial or fungal hydrolases. Transcriptional upregulation of TFEB (master lysosomal biogenesis factor) or TFEB overexpression. Engineer pH-optimized variants of existing lysosomal enzymes. Overexpress other autophagy/lysosomal biogenesis factors. [ATG5 overexpression](https://pmc.ncbi.nlm.nih.gov/articles/PMC3753544/?utm_source=chatgpt.com). [Beclin-1(Becn1) F121A knock-in](https://pmc.ncbi.nlm.nih.gov/articles/PMC5992097/?utm_source=chatgpt.com) to boost autophagy. reverse proteotoxic pathology and lipofuscin via upregulation of lysosome and TFEB programs. +* extracellular crosslinks require the matrix to be replaced or broken (GlycoSENS) via development of crosslink-brakers (such as glucosepane) or refresh extracellular matrix to restore tissue elasticity, especially in arteries. [Glyoxalase-1 (Glo1) overexpression](https://pmc.ncbi.nlm.nih.gov/articles/PMC12382624/?utm_source=chatgpt.com). +* mitochondria DNA mutations need to be bypassed (MitoSENS) by moving mtDNA genes to the nucleus (allotopic expression) and import the proteins back into mitochondria to maintain cellular respiration. Allotopic expression of mitochondrial genes into the nucleus will require recoding for cytosolic translation and also mitochondrial targeting sequences. Mitochondrial-targeted nucleases could be used to eliminate mutant genomes. Therapeutic mitochondrial transplantation or progenitor cell transfer. Engineer enhanced mitochondrial import machinery. Add mitochondrial-targeted DNA repair systems. Overexpress mitochondrial biogenesis factors (PGC-1α, NRF1/2). +* oncogenic nuclear (epi)mutations to pre-empt cancer (OncoSENS) by the "widespread interruption of lengthening of telomeres" to prevent lethal tumor overgrowth, in addition to periodic stem cell reseeding throughout the body; CRISPR/dCas9-based targeted demethylation or histone acetylation to restore youthful gene expression; possibly some epigenetic rejuvenation via transient yamanaka-factor expression for partial reprogramming but i am skeptical. tumor-suppressor genes must not be silenced, in fact they must be unsilenced, and chromatin remodeling errors must be fixed or be made to trigger apoptosis. Immune surveillance to kill pre-cancerous cells. Engineer more robust tumor suppressor networks. Add novel DNA damage sensors and response pathways. [Super p53](https://genesdev.cshlp.org/content/20/1/16.long?utm_source=chatgpt.com) with added extra Ink4/Arf (s-Arf/p53 mice) produced significantly longer lifespan and delayed aging. + +Some of the SENS opportunities can be met via germline engineering: + +* design redundant metabolic pathways to prevent single points of failure +* create "damage-proof" protein variants less prone to aggregation/oxidation +* dramatically upregulate proteostasis networks +* engineer enhanced DNA proofreading and repair machinery, like double-strand break sensor, detection, and repair, or go into apoptosis +* look for better bacterial/archaeal DNA repair systems from other organisms +* metabolic optimization: engineer more efficient electron transport chains with less ROS production +* add alternative respiratory pathways (like those in long-lived animals) +* optimize NAD+ synthesis and utilization pathways +* engineer telomerase regulation for optimal telomere maintenance +* create enhanced stem cell reserves and regenerative capacity +* import longevity genes from extremely long-lived species (bowhead whales, Greenland sharks, naked mole rats) +* add extremophile stress resistance genes +* integrate plant/bacterial antioxidant systems +* damage-resistant proteins? metabolically optimized protein encodings? +* place "stemness" genes (PAX7, LGR5, SOX2, MYC, TERT) under endogenous or synthetic stress-inducible promoters +* maintain larger stem cell pools and create a "progenitor bias" in every tissue, possibly with FOXO3 modifications or upregulation +* probably significantly more opportunities that have long been overlooked. + +## Longevity in other animals + +* C. elegans: daf-2 (insulin/IGF receptor) mutants [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3091520/?utm_source=chatgpt.com) +* C. elegans: age-1 (PI3K); upstream of DAF-16/FOXO [PubMed](https://pubmed.ncbi.nlm.nih.gov/21422498/?utm_source=chatgpt.com) +* C. elegans: intestine-specific degradation of insulin/IGF receptor DAF-2 nearly doubled lifespan; neuronal/hypodermal knockdown gave smaller gains. [Nature](https://www.nature.com/articles/s41467-022-33850-4?utm_source=chatgpt.com) +* Drosophila FOXO/dFOXO activation shows improved lifespan with adipose-like tissue-specific expression. [Fight Aging!](https://www.fightaging.org/archives/2011/03/rasgrf1-deficiency-in-mice-causes-a-20-increase-in-maximum-life-span/?utm_source=chatgpt.com), [Science](https://www.science.org/cms/asset/114abfaf-e857-49e8-8280-1582874b7dad/pap.pdf?utm_source=chatgpt.com) + +Elephants have many extra copies of p53 (TP53) + hyper-responsive DNA-damage signaling. Elephants carry ~20 TP53 retrogenes. Elephant cells trigger apoptosis at lower damage thresholds. ([ref](https://pmc.ncbi.nlm.nih.gov/articles/PMC5061548/?utm_source=chatgpt.com)). "Zombie" pro-apoptotic gene LIF6. A re-functionalized LIF pseudogene (LIF6) is directly upregulated by TP53 after DNA damage and triggers mitochondrial apoptosis, as a second independent tumor-suppression layer ([ref](https://pubmed.ncbi.nlm.nih.gov/30110634/?utm_source=chatgpt.com)). + +bowhead whales: DNA repair & replication factors under selection/duplication. Comparative genomics found bowhead-specific changes in ERCC1 and duplication/lineage-specific changes in PCNA, plus shifts in pathways tied to DNA repair/cell cycle and cancer resistance. ([ref](https://pubmed.ncbi.nlm.nih.gov/25565328/)) + +whales and dolphins: upgrades in tumor suppression. tumor-suppressor genes show positive selection and faster turnover. higher cancer resistance. ([ref](https://pmc.ncbi.nlm.nih.gov/articles/PMC7935004/?utm_source=chatgpt.com)) + +naked mole rats: cancer resistance via extracellular matrix and secretion of very high-molecular-mass [hyaluronan (HMM-HA)](https://www.nature.com/articles/nature12234?utm_source=chatgpt.com). Mechanism ties to p16^INK4a–mediated early contact inhibition. [better proteostasis, proteim homeostasis, and stress resistance](https://www.pnas.org/doi/10.1073/pnas.1313473110?utm_source=chatgpt.com). + +bats: [reduced growth signaling](https://pmc.ncbi.nlm.nih.gov/articles/PMC3753542/?utm_source=chatgpt.com) via GHR/IGF14. [telomere maintenance without age-related shortening](https://pmc.ncbi.nlm.nih.gov/articles/PMC5810611/?utm_source=chatgpt.com). Inflammation braking as a longevity strategy: bats have [dampened cytosolic DNA sensing](https://pmc.ncbi.nlm.nih.gov/articles/PMC7341951/?utm_source=chatgpt.com) (loss of PYHIN genes; STING S358 change), curbing chronic inflammation that drives aging. + +rockfishes: positive selection in DNA-repair pathways. ([ref](https://pmc.ncbi.nlm.nih.gov/articles/PMC8923369/?utm_source=chatgpt.com)) + +galapagos tortoise: DNA repair, mitochondrial homeostasis, enhanced immune pathways. XRC6 variant. + +# additional notes + +* mitochondrial target of rapamycin (mTOR), mTOR inhibitors, etc... +* endocrine niches broadcast longevity or aging signals; you don't need every cell to change, instead targeting key "broadcast" cell types can move systemic aging (fat, endothelium, hypothalamus, skeletal muscle). + +[Big mice die young but large animals live longer](https://pmc.ncbi.nlm.nih.gov/articles/PMC3651517/?utm_source=chatgpt.com) + +[human eunuchs live 14-19 years longer](https://www.sciencedirect.com/science/article/pii/S0960982212007129?utm_source=chatgpt.com) especially when castrated young. [castration delays epigenetic aging](https://pmc.ncbi.nlm.nih.gov/articles/PMC8260231/?utm_source=chatgpt.com) and feminizes DNA methylation patterns. + + + + # Puberty and sexual characteristics erectile dysfunction risk - rs57989773 near 6q16.3 between MCHR2 and SIM1 (<a href="https://www.biorxiv.org/content/early/2018/03/15/283002">ref</a>) @@ -1581,6 +1717,8 @@ Make a general embryological platform for **regeneration**. Salamanders achieve [Transient inactivation of Rb and ARF yields regenerative cells from postmitotic mammalian muscle](https://pmc.ncbi.nlm.nih.gov/articles/PMC2919350/?utm_source=chatgpt.com) +[Lack of p21 expression links cell cycle control and appendage regeneration in mice](https://www.pnas.org/doi/abs/10.1073/pnas.1000830107?utm_source=chatgpt.com) + TODO: maintain primordial pluripotent stem cell pools throughout adult life. TODO: look at salamander cell dedifferentiation capabilities, can we import that into human cells as a switchable capability? |