DAF-16 is a critical longevity assurance gene in C. elegans; in daf-16 mutants, upstream mutations in daf-2-mediated signaling (i.e., the IGF-1 pathway) can’t confer increases in lifespan. In mammals, DAF-16 has several homologs, the FOXO genes, whose roles in aging and lifespan regulation are still being worked out.

Recently we noted an interesting quirk about the worm homolog: DAF-16 is activated by hypergravity, a rather contrived stimulus that probably mimics mechanical stress. It’s a curious connection: What do mechanical stress and aging have in common (other than the no-brainer, “broad-spectrum stress response genes”)?

It turns out that the mechanosensitivity of DAF-16 homologs is conserved across great evolutionary distances; from mammals, we may learn something about the connection between mechanosensitivity and aging. Pardo et al. demonstrate that FOXO activity is responsive to stretching of the diaphragm, and that this responsiveness changes as a function of age:

THE FOXO TRANSCRIPTION FACTORS ARE MECHANOSENSITIVE AND THEIR REGULATION IS ALTERED WITH AGING IN THE RESPIRATORY PUMP

The mechanical regulation of the forkhead box O (FOXO) subclass of transcription factors in the respiratory pump and its implication in aging are completely unknown. We investigated the effects of diaphragm stretch on three FOXO isoforms, FoxO1, FoxO3a and FoxO4 at different ages of normal mice. We tested the hypotheses that 1) FOXO activities are regulated in response to diaphragm stretch and 2) mechanical properties of aging diaphragm are altered leading to altered regulation of FOXO with aging. Our results showed that stretch downregulated FOXO DNA binding activity by a mechanism that required Akt and IkappaB kinase (IKK) activation in young mice but loss of mechanosensitive of these pathways occurred with age. This aberrant regulation of FOXO with aging was associated with altered viscoelasticity, compliance and extensibility of the aged diaphragm. Curiously, the nuclear content of Foxo1 and Foxo3a , the two isoforms associated with muscle atrophy, diminished dramatically with aging in correlation with higher basal activation of Akt and IKK signaling in diaphragms of old mice . In contrast, the stability of Foxo4 in the nucleus became dependent on JNK, which is strongly activated in aged diaphragm. This suggested that Foxo4 was responsible for the FOXO-dependent transcriptional activity in aging diaphragm. Our data supported the hypothesis that aging alters the mechanical properties of the respiratory pump leading to altered mechanical regulation of the stretch-induced signaling pathways controlling FOXO activities. Our study supports a mechanosensitive signaling mechanism that is responsible for the regulation of the FOXO transcription factors by aging.

Note the feedback operating here: Over the course of aging, the elasticity of the diaphragm changes, which in turn alters the nature of the mechanical forces operating on the smooth muscle cells that both bear load and generate force. FOXOs are mechanosensitive, but the changing structure of the tissue (and concomitantly changing nature of the forces it experiences) means that the signals they’re responding to will change over the course of the lifespan. This relationship opens a related question: To what extent does the gene expression output of FOXO transcription factors feed back on the structural and elastic properties of the diaphragm?

Take a deep breath…