Cellular aging shows up as a set of hallmarks shared across species: genome instability, telomere shortening, epigenetic changes, and cellular senescence. Recent data suggest that changes in the nucleus itself may be a new hallmark of aging. This is especially clear in progeria, a premature aging syndrome caused by the accumulation of a defective protein, prelamin A, which disrupts the mechanical properties of the nucleus. In physiological aging, prelamin A does not accumulate, yet cells show the same nuclear changes as in progeria. A key player here is the protein SUN1, a component of the LINC complex that links the nucleus to the cytoskeleton. Elevated SUN1 levels are characteristic of both progeria and normal aging, and removing it in progeria mice extends lifespan and improves tissue condition. However, the mechanism linking SUN1 to aging remained unknown. This work sits at the intersection of cellular aging, mechanotransduction, and systemic blood factors: it shows how a secreted protein triggers an intracellular aging mechanism through a nuclear bridge.
To find out how aging cells affect their neighbors, the authors used a culture version of parabiosis, the shared housing of young and old animals. They treated young fibroblasts with medium from old cells and vice versa, then assessed cell polarization: the movement of the nucleus backward and the orientation of the centrosome in response to stimulation with lysophosphatidic acid. To identify the polarization inhibitor, they subjected the old-cell medium to biochemical treatments: heating, dialysis, protease treatment, and RNase treatment. They compared the protein composition of the media using mass spectrometry with tandem mass tags. To study the mechanism of ApoD action, they used SUN1 knockdown with shRNA, inhibitors of dynein and deacetylase, and expression of mutant forms of SUN1 and fragments of nesprin-2. Transcriptome analysis was done by RNA-Seq, and chromatin accessibility was assessed with ATAC-Seq. The effect of ApoD on muscle regeneration was tested in mice with barium chloride-induced muscle injury.
Medium from old fibroblasts suppressed the polarization of young cells, while medium from young cells did not improve the polarization of old ones. The inhibitor turned out to be a protein: it did not pass through dialysis, was destroyed by heating and protease treatment, but not by RNase. Mass spectrometry revealed that the level of the protein ApoD was elevated in the old-cell medium (2.9-fold). Recombinant ApoD at concentrations typical of plasma suppressed fibroblast polarization. ApoD did not block the action of lysophosphatidic acid but instead caused long-term changes: it raised the level of the SUN1 protein without affecting its mRNA, which pointed to protein stabilization. Suppressing SUN1 or inhibiting dynein and microtubule deacetylation canceled the effect of ApoD. Expression of wild-type SUN1, but not of a mutant unable to bind nesprins, increased ApoD secretion. Knockdown of nesprin-2 reduced Apod expression and altered the expression of 356 genes; restoring the expression of a nesprin-2 fragment that binds microtubules, but not actin, brought back Apod expression and chromatin accessibility at the gene promoter. Elevated SUN1 levels and ApoD treatment caused additional signs of aging: a drop in lamin B1, a decrease in the histone mark H3K9me3, a fall in mitochondrial membrane potential, and a rise in reactive oxygen species. In a mouse model, ApoD worsened muscle recovery after injury: muscle mass and the force of single and tetanic contraction were lower than in control animals.
The work shows for the first time that the secreted protein ApoD and the nuclear protein SUN1 form a positive feedback loop that accelerates cellular aging. Unlike neighboring studies focused on epigenetics, cellular senescence, or individual aspects of mechanotransduction, this paper links a systemic blood factor to an intracellular mechanism through the LINC complex and microtubules. What is fundamentally new is the discovery of a direct pathway by which microtubules regulate gene expression through the LINC complex, rather than through the actin cytoskeleton as previously assumed. This changes the picture of mechanotransduction and explains why aging accelerates after age 60: the feedback loop may synchronize the aging of cells within a tissue.
In the future, it will be important to determine what triggers the ApoD-SUN1 loop during physiological aging. Chronic inflammation, which stimulates ApoD production, may be the trigger. Another direction is to study the crosstalk between the microtubule pathway and other mechanosensitive pathways, for example those involving phospholipase cPLA2 and arachidonic acid. It also remains to be tested whether this loop operates in other cell types and tissues, and whether it can be broken pharmacologically to slow aging.
The results could influence gerontology, regenerative medicine, and research on systemic aging factors. ApoD and SUN1 are becoming potential targets for treating age-related disorders, especially muscle weakness and delayed wound healing.
The immediate steps include identifying the triggers of the ApoD-SUN1 loop, testing its role in other tissues, and searching for inhibitors capable of breaking the loop. It is also necessary to study how microtubules transmit mechanical signals to chromatin.
The work is directly tied to an unsolved problem in gerontology: why aging accelerates at a certain age and how systemic factors coordinate the aging of different tissues. The discovery of the ApoD-SUN1 loop provides a concrete molecular mechanism to explain the synchronization of aging. In addition, the paper raises the question of which other genes are regulated by microtubules through the LINC complex, which may be a general principle of mechanotransduction.
The protein ApoD (apolipoprotein D) was first discovered as a component of high-density lipoproteins, but its exact function long remained a mystery. It turned out to be produced in the brain in Alzheimer's disease and to protect neurons from oxidative stress. Now it turns out that ApoD is also an aging factor that old cells send to young ones to make them "grow old" too.
The idea that aging can be transmitted through blood brings to mind Aldous Huxley's novel Brave New World, where people age and die on a schedule. In reality, the mechanism turned out to be subtler: not just an "aging factor" in the blood, but a feedback loop that amplifies itself.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.