Aging remains one of the greatest mysteries in biology. Among the many hypotheses explaining this process, the theory of accumulated DNA damage holds a special place. A study published in the journal Cell sheds light on the evolutionary mechanisms linking the efficiency of double-strand break (DSB) repair in DNA to the maximum lifespan (MLS) of mammals. Researchers from the University of Rochester (USA) conducted a large-scale comparative analysis of 18 rodent species, revealing the critical role of the protein SIRT6 in maintaining genomic stability and determining species longevity.
DNA Repair and Aging: Two Pathways, Two Fates
DNA damage is an inevitable consequence of metabolic processes and external factors. Among all types of damage, double-strand breaks (DSBs) are considered the most dangerous, as their improper repair can lead to chromosomal rearrangements, oncogenesis, and cellular aging. Evolution has "taught" organisms to combat these damages through two main mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ). However, it remained unclear how these systems are linked to species-specific lifespan.
Using a unique panel of 18 rodent species with MLS ranging from 3 to 32 years (e.g., mice – 4 years, naked mole rats – 32 years), scientists conducted a systematic analysis of two key repair pathways:
· Nucleotide Excision Repair (NER), which removes UV-induced damage.
· DSB repair via NHEJ and HR.
The results were surprising:
NER did not correlate with MLS but depended on the level of sunlight exposure. Diurnal species (e.g., squirrels) demonstrated more efficient NER than nocturnal (blind mole rats) or subterranean (naked mole rats) species. This was confirmed in survival tests after UV irradiation (LD50 for highly active species was 180 J/m² compared to 60 J/m² for less active ones).
DSB repair, on the other hand, strongly correlated with longevity. In long-lived species like beavers (MLS = 24 years), the efficiency of NHEJ and HR in skin and lung fibroblasts was 3–5 times higher than in short-lived mice. For example, after 8 Gy of γ-irradiation, beaver cells eliminated 90% of γH2AX/53BP1 foci within 24 hours, whereas mouse cells eliminated only 50%.
SIRT6: The Molecular "Conductor" of DSB Repair
To uncover the mechanism behind enhanced DSB repair in long-lived species, researchers focused on sirtuin 6 (SIRT6), a protein from the NAD⁺-dependent deacetylase family known for its role in genome stabilization. Previous studies showed that SIRT6 activates PARP1, a critical enzyme in DSB repair, and its overexpression extends the lifespan of mice.
A comparative analysis of SIRT6 across the 18 species revealed:
o The activity of SIRT6 in stimulating NHEJ and HR strongly correlates with MLS (r² = 0.54–0.64). For instance, the beaver's SIRT6 increased NHEJ efficiency in mouse cells by 4.2 times, while the mouse SIRT6 did so by only 1.5 times.
o Evolutionary changes were concentrated in the C-terminal domain of the protein. Substituting just five amino acids (H235Q, Q249H, E260K, T263S, R264Q) transformed the "weak" mouse SIRT6 into a "strong" beaver-like version, and vice versa. These amino acids are located on the protein's surface, influencing its binding to nucleosomes and enzymatic activity.
Biochemical experiments confirmed that the beaver’s SIRT6 exhibits enhanced:
· Deacetylase activity toward histone marks H3K9ac, H3K18ac, and H3K56ac.
· Substrate affinity: Km for NAD⁺ in the beaver’s SIRT6 was 138.6 µM compared to 150.9 µM in the mouse version.
From Lab to Longevity: SIRT6 in Action
To test the physiological significance of these differences, researchers conducted experiments on cell models and Drosophila melanogaster :
• Cellular aging: Knockout of SIRT6 in human fibroblasts sharply increased sensitivity to γ-irradiation and the number of β-galactosidase-positive (senescent) cells. However, expressing the beaver’s SIRT6 reduced the fraction of senescent cells after 5 Gy irradiation from 60% to 20%, while the mouse protein reduced it only to 45%.
• Lifespan extension in flies: Transgenic lines expressing the beaver’s SIRT6 under an inducible promoter showed a 17.7% increase in median lifespan (from 56 to 73 days) when activated in adult individuals. Replacing the five key amino acids reduced this effect to 8.9%.
Evolutionary and Medical Implications
This study demonstrates for the first time that natural selection has optimized DSB repair in long-lived species by enhancing the functions of SIRT6. Interestingly, such changes arose convergently in unrelated species (e.g., beavers and naked mole rats), highlighting the universality of this mechanism.
The practical applications of this discovery are multifaceted:
o Developing activators of SIRT6 that mimic "longevity-enhanced" variants could become a new strategy in combating age-related diseases and cancer.
o Genetic screening for polymorphisms in the SIRT6 gene may help predict individual susceptibility to aging.
o Rodent models with "enhanced" SIRT6 could allow testing of anti-aging therapies.
"Our study shows that evolution has already found ways to optimize DNA repair for longevity. Now the challenge is to translate these solutions into medicine," concludes Vera Gorbunova, co-author of the study.
Conclusion
The discovery of five amino acids determining SIRT6 activity not only deepens our understanding of the molecular foundations of aging but also opens the door to targeted modulation of this protein. In the future, this could lead to therapies that slow aging and reduce cancer risks by enhancing innate mechanisms of genome protection.
Publication date: 02.06.2024
Source:
Tian X. et al. SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species. Cell. 2019 Apr 18;177(3):622-638.e22. doi: 10.1016/j.cell.2019.03.043. PMID: 31002797; PMCID: PMC6499390.