#1

Hello,

does anyone have access to this paper please ? : Targeting DNA damage in ageing: towards supercharging DNA repair | Nature Reviews Drug Discovery

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#2

Bujarrabal-Dueso.pdf (2.6 MB)
Here you go.

4 Likes
#3

Here is an AI summary of conclusions:
Overview

The document discusses the role of DNA damage in aging and explores therapeutic strategies to enhance DNA repair mechanisms to combat age-related diseases.

What are the most effective methods of preventing and repairing DNA damage?

The document outlines several effective methods for preventing and repairing DNA damage, categorized into pharmacological, genetic, and therapeutic approaches:

1. Pharmacological Approaches

  • Senolytics and Senomorphics: Drugs like dasatinib, quercetin, fisetin, and luteolin selectively eliminate senescent cells or suppress their harmful secretory phenotype (SASP), reducing inflammation and DNA damage-related effects.
  • NAD+ Supplementation: NAD+ precursors (e.g., nicotinamide riboside, nicotinic acid) enhance DNA repair by supporting PARP and sirtuin activity, which are critical for repairing single-strand breaks and maintaining genomic stability.
  • SIRT6 Activation: Compounds like UBCS039 activate SIRT6, improving double-strand break repair and extending healthspan.
  • cGAS-STING Inhibitors: Drugs such as hydroxychloroquine, quinacrine, and VENT-03 inhibit the inflammatory response triggered by cytosolic DNA, reducing chronic inflammation associated with DNA damage.
  • DNA Repair Enzymes: Photolyase and T4 endonuclease V, applied topically, repair UV-induced DNA damage in the skin.
  • DYRK1A Inhibitors: Harmine and other inhibitors target the DREAM complex, boosting the expression of DNA repair genes across all major repair pathways.

2. Genetic and Cellular Approaches

  • Gene Therapy: CRISPR-Cas9 and adenine base editors have been used to correct mutations in DNA repair genes, such as those causing progeroid syndromes like Hutchinson-Gilford progeria and Cockayne syndrome.
  • Cellular Reprogramming: Partial reprogramming with Yamanaka factors reverses epigenetic aging and promotes DNA repair, potentially rejuvenating cells.

3. Lifestyle and Dietary Interventions

  • Calorie Restriction: Reduces DNA damage load and improves transcriptional fidelity, as shown in progeroid mouse models.
  • Antioxidants: Compounds like fucoidan and piperlongumine reduce oxidative stress, which is a major source of DNA damage.

4. Emerging Strategies

  • DREAM Complex Inhibition: Targeting the DREAM repressor complex enhances DNA repair capacity, mimicking germline-like repair mechanisms in somatic cells.
  • Exosome-Based Delivery: Extracellular vesicles loaded with nucleases (e.g., S1 nuclease, RNase H) remove cytosolic DNA fragments, reducing inflammation and neurodegeneration.

These methods collectively aim to prevent DNA damage, enhance repair mechanisms, and mitigate the consequences of genomic instability, offering promising avenues for anti-aging and disease prevention therapies.

3 Likes
#4

A paper worth looking at:

https://www.nature.com/articles/s41586-024-08423-8

Among other things it seems to imply that there are certain DNA mutations that could be repaired (not all types of mutations can be) that persist for hours, days, weeks… even years. These uncorrected mutations can lead to even more mutations later on.

It seems that just even fixing this problem of potentially correctable DNA mutations could have healthspan and potentially lifespan-extending effects.

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#5

There is a new startup focused on DNA repair. Alan Tomusiak is the founder - he came out of the Age1 VC company, and I think they may be onto something really interesting. I spoke with Alan at the Longevity Summit last December… he’s found some molecules that seem to substantially protect DNA from double strand breaks … so something that could really help with DNA stability over the longterm, given radiation damage from the Sun to the skin, etc. Watch this company going forward…

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