Hormesis triggers reversible lamin A/C‑mediated chromatin silencing that suppresses quasi‑programmed aging via ATM‑dependent mechanotransduction

Hypothesis

Mild intermittent stress activates ATM‑dependent phosphorylation of lamin A/C, causing a transient stiffening of the nuclear lamina that represses chromatin domains driving anabolic growth programs. This mechanochemical signal mimics the downstream effect of quasi‑programmed aging suppression without requiring actual damage accumulation, thereby explaining why hormetic interventions extend lifespan only modestly and in an inverted‑U fashion.

Mechanistic Rationale

• Hormetic stimuli (cold, fasting, low‑dose radiation, exercise) generate sub‑lethal increases in intracellular ROS and Ca²⁺ fluxes that activate the ATM kinase independently of DNA double‑strand breaks (1).
• ATM phosphorylates lamin A/C at serine 22, promoting lamin polymerization and nuclear envelope rigidity (2).
• A stiffer lamina limits the mobility of transcription factors such as SREBP‑1c and mTORC1 regulators, reducing their access to growth‑promoting gene loci (3).
• The resulting transcriptional dampening lowers TOR‑driven quasi‑programmed aging signaling, extending lifespan by the same 16‑25 % range observed for daf‑16/skn‑1 dependent hormesis (4).
• Because the lamina change is reversible, repeated mild stress yields a cyclic “window of quiescence” that resets growth signaling without triggering repair pathways, reconciling the observation that acute stress‑marker activation alone (e.g., menadione) does not guarantee longevity.

Testable Predictions

1. Pharmacological inhibition of ATM (e.g., with KU‑55933) or expression of a non‑phosphorylatable lamin A/C mutant (S22A) will abolish the lifespan extension caused by hormetic treatments, while leaving acute ROS or HSP‑70 induction unchanged.
2. In C. elegans, RNAi of lmn‑1 (lamin homolog) or expression of a phospho‑deficient LMN‑1::S22A will suppress the daf‑16‑dependent longevity boost from intermittent fasting or low‑dose juglone.
3. Live‑cell imaging of lamin A/C FRET tension sensors will show a transient increase in nuclear membrane tension during hormetic exposure that returns to baseline within 2–4 h, correlating with downstream reduction in phospho‑S6K levels.
4. Chromatin accessibility assays (ATAC‑seq) performed after hormetic pretreatment will reveal decreased openness at promoters of ribosomal protein and lipid synthesis genes, an effect lost when ATM is inhibited.

Experimental Approach

• Model systems: Use C. elegans strains carrying lmn‑1::GFP and a phospho‑specific antibody, plus mammalian fibroblast lines expressing lamin A/C‑FRET tension sensors.
• Treatments: Apply intermittent cold (15 °C for 30 min twice daily), 2‑deoxy‑glucose fasting pulses, or low‑dose plumbagin (0.5 µM) for 24 h, matching published hormesis regimens.
• Readouts: Lifespan curves, ROS/HSP‑70 levels (to confirm stress marker activation), phospho‑lamin A/C (Western), nuclear tension (FRET), ATAC‑seq, and phospho‑S6K/TOR activity.
• Controls: Include menadione treatment (high ROS, no longevity) to verify that ATM‑lamin signaling is dissociated from generic stress responses.

Falsifiability

If ATM inhibition or lamin A/C S22A mutation fails to diminish hormetic lifespan extension despite normal activation of ROS/HSP‑70 reporters, the hypothesis is falsified. Conversely, if lamin tension changes are absent or chromatin accessibility remains unaltered under conditions that still extend life, the proposed mechanotransductive link would be refuted.