April 30, 2026
Today’s Horizons in Biosciences and Informatics Seminar series (HBISS) featured Drs. Vera Gorbunova and Andrei Seluanov of the University of Rochester on the comparative biology of aging, with a direct line through to protecting astronaut genome integrity on long-duration missions. 
Here is the link to view the recording if you were unable to join.
What Andrei covered
Andrei opened Part 1 with the comparative biology framework: mammals span roughly 100x in maximum lifespan, from the two-year shrew at one end to the 211-year bowhead whale at the other. The naked mole rat (~41 years), long-lived bat species (30 to 40 years), blind mole rats, and several rodent lineages sit in between. The premise of comparative biology of aging is straightforward. Find the genes and pathways that let these species outlive mice, then translate those findings into interventions that extend healthspan and lifespan in humans.
He walked through the Rochester group’s pipeline, built around tissues and primary cells from around 50 mammalian species. From that collection, the team has zeroed in on roughly six long-lived mammals (bowhead whale, naked mole rat, blind mole rat, squirrels, bats, with elephants added through collaboration) and identified distinct longevity-related pathways in each. Andrei flagged this as an open question for the field: nature has selected a striking variety of longevity strategies, and we do not yet know how many such pathways exist.
The first deep dive was the naked mole rat (NMR), the longest-lived rodent, with a maximum lifespan around 41 years (compared to ~4 years in the house mouse) and an unusual resistance to cancer. Multi-year observations of large NMR colonies failed to detect a single tumor.
The Rochester group identified high-molecular-weight hyaluronan (HMW-HA) as the mediator:
- NMR fibroblasts secrete HA more than five times larger than human or mouse HA, and HMW-HA accumulates abundantly in NMR tissues
- Two reasons for the accumulation: NMR HA-degrading enzymes are less active, and the HAS2 hyaluronan synthase carries a distinctive sequence
- NMR cells also signal more sensitively in response to HA, so the molecule reaches its targets more effectively
- Perturb the system (knock down HAS2, or overexpress the HA-degrading enzyme HYAL2) and NMR cells become susceptible to malignant transformation and readily form tumors when transplanted into mice
The team’s interpretation: HMW-HA likely evolved first to give NMR skin the elasticity needed for life in underground tunnels, and that trait was then co-opted into a cancer resistance and longevity mechanism. Tian et al. 2013, Nature: https://doi.org/10.1038/nature12234
The naked mole rat sets up the throughline for Part 2. A different long-lived mammal, a different evolved strategy, the same translational question for human and astronaut health.
What Vera covered
Vera picked up Part 2 with the bowhead whale, then SIRT6 across rodents and human centenarians, and finished by opening the transposable element thread.
Bowhead whale: repair fidelity over cell elimination
At more than 200 years, the bowhead whale is the longest-lived mammal on Earth and also one of the largest, exceeding 80,000 kg. With that many cells over that many years, the bowhead should be a cancer factory. It isn’t. That mismatch is the canonical statement of Peto’s Paradox: large, long-lived animals do not face proportionally elevated cancer risk despite their massive cell counts. Caulin & Maley 2011: https://doi.org/10.1016/j.tree.2011.01.002
Different long-lived species resolve Peto’s Paradox differently. Elephants stack the deck on tumor suppressor genes (extra TP53 copies) and lean on enhanced cell death to eliminate damaged cells. Bowheads do the opposite. As Vera framed it, if you plan to live for 200 years you cannot just keep killing cells, you will run out. The bowhead instead emphasizes maintenance: repair the damage faithfully and keep the cell.
Counterintuitively, bowhead fibroblasts actually require fewer oncogenic hits to undergo malignant transformation than human fibroblasts. They make up for it on the back end with dramatically superior DNA double-strand break (DSB) repair fidelity and a lower mutation rate than other mammals studied. The mechanistic finding is cold-inducible RNA-binding protein (CIRBP), expressed at very high levels in bowhead fibroblasts and bowhead tissues.
Bowhead CIRBP, when expressed in human cells:
- enhances both non-homologous end joining (NHEJ) and homologous recombination (HR) DSB repair
- reduces micronuclei formation
- promotes DNA end protection
- stimulates end joining in vitro
In Drosophila, bowhead CIRBP overexpression extends lifespan and improves resistance to ionizing radiation, a striking cross-species transferability for a single repair-fidelity factor.
Vera also walked through what is distinctive about the bowhead version of CIRBP at the sequence level. The bowhead protein carries amino acid repeat patterns (including 5-residue patterns that came up in audience Q&A) that may shape RNA binding and function, and the bowhead transcript carries synonymous codon changes that increase translation efficiency relative to the human ortholog. Firsanov et al. 2025, Nature: https://doi.org/10.1038/s41586-025-09694-5
The spaceflight relevance is direct. Astronauts beyond LEO accumulate ionizing radiation damage at accelerated rates from galactic cosmic rays, including high-energy heavy ions like iron and silicon that produce clustered, complex DSBs. Repair fidelity, not just repair speed, is the lever that matters for protecting genome integrity on long-duration missions. CIRBP is the kind of factor that maps cleanly onto that need.
SIRT6: longevity and double-strand break repair
Vera pivoted to SIRT6, a chromatin-associated protein the Rochester group has worked on for many years. SIRT6 sits at a hub where several genome-protection functions converge: it deacetylates histones, supports DSB repair, maintains the epigenome, silences genes, and suppresses transposable elements. The genetic phenotypes match its central role. SIRT6 knockout mice die prematurely with progeroid features. SIRT6 overexpression extends lifespan.
In a panel of 18 rodent species spanning a wide range of maximum lifespans, DSB repair efficiency, but not nucleotide excision repair (NER), co-evolves with longevity. NER appears to be shaped primarily by sunlight exposure rather than lifespan. SIRT6 sits at the center of the DSB signal: SIRT6 enzymatic activity is weak in short-lived rodents like the mouse and strong in long-lived rodents like the beaver. The team narrowed the activity difference down to five specific amino acid residues. Swap those five residues from the beaver protein into mouse SIRT6, and the mouse protein becomes as robust as the beaver version. Tian et al. 2019, Cell: https://doi.org/10.1016/j.cell.2019.03.043
The pattern then jumps from rodents into humans. In collaboration with Yousin Suh’s group at Albert Einstein College of Medicine, the Rochester team tested SIRT6 variants found in human centenarians (people who live to 100 and beyond). The centenarian SIRT6 variant produces more efficient DNA repair and better genome protection in functional assays. So stronger SIRT6 activity tracks with longer lifespan both across rodent species and within our own, a tidy evolutionary convergence on the same DSB-repair-as-longevity-driver finding from the bowhead.
Transposable element suppression
Vera closed by opening the transposable element thread. Protein-coding genes make up only ~1% of the mammalian genome. The rest is dominated by repetitive elements, including LINE1 retrotransposons that need active suppression throughout life. SIRT6 is one of the proteins that holds those elements in check, and loss or weakening of TE suppression with age is increasingly recognized as a driver of inflammaging and senescence. The thread ties directly back to spaceflight, where retrotransposon activation appears in astronaut samples and could be a target for SIRT6- or CIRBP-style countermeasures.
The talk continued from there into questions and discussion.
Key discussion highlights
- Parvathy J @Parvathy_J asked whether the amino acid repeats and 5-residue patterns in CIRBP confer structural advantages for RNA binding or functionality of the whale CIRBP.
- Madhan Tirumalai @mrtirum2 brought in the yeast side: Sir2 / sirtuin / NAD+ / caloric restriction as a metabolic-sensor longevity axis (Wierman & Smith 2014: Yeast Sirtuins and the Regulation of Aging - PMC; Lin et al. 2004: https://genesdev.cshlp.org/content/18/1/12.full), and noted that simulated microgravity accelerates aging in budding yeast through altered histone deacetylase function — a possible bridge to Sir2/SIRT6 orthologs in spaceflight contexts.
- Amanda Saravia-Butler @asaravia asked about the increased translation efficiency of bowhead CIRBP from synonymous codon changes, and whether equivalent synonymous changes have been tested in human CIRBP RNA for translation efficiency and mRNA stability.
- Lynn Harrison flagged whether the bowhead repair assays used clean breaks rather than complex (clustered) DSB damage, the latter being the dominant lesion type from HZE ions and galactic cosmic rays. She also noted that mycobacteria carry NHEJ machinery but E. coli do not.
- Elizabeth Aslinger @dr.aslinger raised biphasic response framing: how to think about cases where both under- and over-activation of a gene drive a similar bad outcome through shared mediators like inflammation feeding into senescence and damage.
- Charles Naney @ccnaney asked how many bowhead whales were screened for tumors.
- Ryan Scott @rtscott2001 asked which translational route looks most promising for protecting genome integrity in high-radiation populations, including astronauts: mRNA, AAV, or small-molecule activators.
Next HBISS
May 18, 2026: RR8 (Rodent Research-8) science and data 
Watch Forum-Space for the speaker and details.
All links from the chat and presentation
- Bowhead whale Nature paper (Firsanov et al. 2025) — https://doi.org/10.1038/s41586-025-09694-5
- Bowhead paper Data Availability section (if AWGers want to investigate CIRBP on OSDR) — https://www.nature.com/articles/s41586-025-09694-5#data-availability
- Naked mole rat hyaluronan (Tian et al. 2013) — https://doi.org/10.1038/nature12234
- SIRT6 in long-lived rodents (Tian et al. 2019) — https://doi.org/10.1016/j.cell.2019.03.043
- Peto’s Paradox (Caulin & Maley 2011) — https://doi.org/10.1016/j.tree.2011.01.002
- CIRBP regulation review (Corre & Lebreton 2023) — https://doi.org/10.1016/j.biochi.2023.04.003
- Yeast sirtuins and aging — https://pmc.ncbi.nlm.nih.gov/articles/PMC4365911/
- Caloric restriction and yeast lifespan (Lin et al. 2004) — https://genesdev.cshlp.org/content/18/1/12.full
- Vera Gorbunova Google Scholar — https://scholar.google.com/citations?user=ZKlFrUIAAAAJ&hl=en
- Andrei Seluanov Google Scholar — https://scholar.google.com/citations?user=2KHusF4AAAAJ&hl=en
- AWG Forum-Space About — https://awg.osdr.space/about
