Curing Aging in the Near Future
Blood cancers
Cancer therapy (OVERCOME)
A potentially better option than CAR T-cells for solid tumors.
"Oncolytic Vector Efficient Replication Contingent on Omnipresent Mutation Engagement" (OVERCOME).
1. Renteln M. Conditional replication of oncolytic viruses based on detection of oncogenic mRNA. Gene Therapy (2018) 25:1–3. doi: 10.1038/gt.2017.99.
2. Renteln M. Correction: Conditional Replication of Oncolytic Viruses Based on Detection of Oncogenic MRNA. Gene Ther 2021;28(7):469–469; doi: 10.1038/s41434-020-00216-8.
3. Renteln M. Promoting Oncolytic Vector Replication with Switches that Detect Ubiquitous Mutations. CCTR 2024;20:40–52. https://doi.org/10.2174/1573394719666230502110244.
Preprint: https://www.preprints.org/manuscript/202208.0220/v1
4. Renteln M. Targeting Clonal Mutations with Synthetic Microbes 2024. https://www.preprints.org/manuscript/202308.1536/v11.
Targeting senescent cells
Preventing DNA damage and mutations
Plaque reduction
Lipofuscin, i.e., indigestible intracellular garbage, might be the main driving force of current age-related disease. However, there may be a way that we can remove lipofuscin from our bodies in the near future.
*Crucial information:
A. To be able to fix nuclear DNA mutations and mitochondrial DNA mutations in the future, we must have reference sequences that are as pristine, i.e., close to the individual’s original sequences, as possible. This means that ideally we would sequence our nuclear and mitochondrial genomes when we are as young as possible.
However, having a few mutations scattered throughout our sequenced genomes may not matter too much.
B. We also may want to freeze some of our cells with relatively pristine DNA, so that we can dedifferentiate them to iPSCs and then generate hematopoietic stem cells (HSCs), monocytes, and/or macrophages in the future, if we need to enact whole-body induced cell turnover* prior to our ability to print entire nuclear genomes.
The HSCs, monocytes, and/or macrophages would be used to replace our tissue-resident macrophages with edited versions that can accomplish therapeutic tasks.
First, it would be whole-body lipofuscin removal, and second would be adult stem cell replacement with edited versions that can enact whole-body induced cell turnover.
1. Renteln M. Toward systemic lipofuscin removal 2024. https://www.liebertpub.com/doi/10.1089/rej.2024.0034.
Preprint: https://www.preprints.org/manuscript/202208.0229/v9.
Note:
To increase the efficiency of Metagenomic Alteration of Gut microbiome by In situ Conjugation (MAGIC)*, a chain reaction can be effected by transfer of the IncPα-family RP4 conjugation system genes in addition to the cargo genes.
*https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467691/
For biocontainment purposes, at the very least, transfer of the plasmid encoding all the necessary elements can be made dependent on a small molecule.
Relevant papers:
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658125/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6126907/
Anti-aging therapy - whole-body lipofuscin removal
Mitochondrial DNA replacement
Mitochondrial transplantation via edited TRMs:
Arrestin domain containing protein 1 [ARRDC1]-mediated microvesicles (ARMMs) could be employed to transfer mitochondria to aged cells with mitochondria that have mutated/damaged* DNA [1,2].
*Damaged mtDNA can be fixed via mitophagy.
PGC-1α could be overexpressed by the edited TRMs to increase their intracellular stores of mitochondria [3].
Miro1 overexpression might help to improve donation efficiency [4].
These mitochondria could be imbued with synonymous mutations that allow for targeting of aged mitochondrial DNA with pre-imported nucleases [5]. Alternatively, COURIER could be used in combination with ARMMs. COURIER might work better than pre-imported nucleases because it would not rely on target cell mitochondrial fusion-fission dynamics.
1. Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun 2015;6:8472; doi: 10.1038/ncomms9472.
2. Wang Q, Yu J, Kadungure T, et al. ARMMs as a versatile platform for intracellular delivery of macromolecules. Nat Commun 2018;9(1):960; doi: 10.1038/s41467-018-03390-x.
3. Ventura-Clapier R, Garnier A, Veksler V. Transcriptional control of mitochondrial biogenesis: the central role of PGC-1α. Cardiovascular Research 2008;79(2):208–217; doi: 10.1093/cvr/cvn098.
4. Ahmad T, Mukherjee S, Pattnaik B, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. The EMBO Journal 2014;33(9):994–1010; doi: 10.1002/embj.201386030.
5. Shoop WK, Lape J, Trum M, et al. Efficient elimination of MELAS-associated m.3243G mutant mitochondrial DNA by an engineered mitoARCUS nuclease. Nat Metab 2023;5(12):2169–2183; doi: 10.1038/s42255-023-00932-6.
Gene editing/therapy
AAV
1. https://www.nejm.org/doi/full/10.1056/NEJMoa1706198
2. https://www.nature.com/articles/s41565-023-01419-x
HSCs
1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10111954/
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11399618/
"COURIER" or "SPIT" with tissue-resident macrophage (TRM) replacement
1. "COURIER": https://pubmed.ncbi.nlm.nih.gov/37437570/
2. "SPIT": https://www.biorxiv.org/content/10.1101/2024.01.11.575257v1
3. Microglial replacement 1: https://pubmed.ncbi.nlm.nih.gov/35294256/
4. Microglial replacement 2: https://pubmed.ncbi.nlm.nih.gov/37541210/
5. TRM replacement 1: https://pubmed.ncbi.nlm.nih.gov/32900927/
6. TRM replacement 2: https://pubmed.ncbi.nlm.nih.gov/37748049/
Precluding or curing infections
Broad-spectrum antiviral strategy:
1. Systemic DRACO (https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022572) installation via secretion of DNA or reverse transcribing RNA constructs by edited TRMs.
A HIV proviral genome-excising recombinase (that is seemingly non-immunogenic):
1. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298542
HIV ex vivo gene editing:
1. https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00083-3
Eliminating drug-resistant pathogens:
1. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00026-9/fulltext
--> broad-spectrum antibiotic that does not evoke resistance
2. Inducible secretion of infection-fighting agents like antimicrobial peptides by edited TRMs.
Central and peripheral tissue regeneration/replacement
1. Transplantation of stem cell-derived neurons (although this paper is specifically about Parkinson's disease - which may be reversed/prevented mostly by lipofuscin removal) → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796915/
2. Spinal cord injuries → https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8723833/ + https://www.science.org/doi/10.1126/science.adi6412
Subatomic reconstruction
CONTACT
Hi - I'm a California-based longevity enthusiast.
If you have any questions or comments about the anti-aging science you see here, please feel free to contact me at info.eliminateaging@gmail.com!
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