Microtubule Function and Longevity in Nematodes
Researchers here report on genetic manipulations that alter the function of microtubules in the cells of nematode worms and thereby cause increased longevity. Microtubules help to support cell structure, and act as pathways to allow movement of structures and molecules around the cell. The effect on longevity appear to be mediated via improved or altered function of neurons, leading to alterations in metabolism of a sort already known to influence life span in this species. The degree to which this is relevant to aging in higher organisms remains to be established, but as a general rule one should expect ever smaller effect sizes for this sort of thing as one moves to test in larger and longer-lived species. Short-lived species have lifespans that are very plastic in response to metabolic stress and environmental change, while long-lived species do not.
Microtubules (MTs) play fundamental roles in cellular functions including cell division, cell shape, and intracellular transport. Abnormal MT regulation has been linked to age-related disorders and diseases, and MTs often serve as targets for disease therapies. MT regulation is particularly important for neurons, since their polarized morphologies dictate heavy reliance on MT function for their maintenance. MT regulation is involved on several levels in neuronal function and maintenance of neuronal structure, and also appears to be a general downstream indicator and effector in age-dependent neurodegeneration.
The nervous system modulates lifespan in various species. It detects sensory cues from the environment and internal signals from the animal, and coordinates organismal metabolic homeostasis and energy balance. Different neuron types respond to distinct cues to extend or shorten lifespan through activating distinct neuronal signals and signaling pathways, including the insulin/insulin-like growth factor-1 signaling (IIS) pathway, which plays an evolutionarily conserved role in regulating lifespan. Despite the essential role of MTs in neuronal function and the central role of the nervous system in regulating longevity, MT regulation has not been directly linked to lifespan modulation.
We have recently reported that mutations in MT regulators can affect lifespan in a DAF-16 dependent manner. We found that loss of EFA-6, a protein promotes MT catastrophe, increased mean lifespan of C. elegans and delayed age-associated changes in neuronal integrity, such as axon blebbing and branching as well as mislocalization of synaptic vesicles to dendritic structures within touch sensory neurons. The effects of the loss of EFA-6 opposed those effects seen with the loss of PTL-1, the worm homolog of human Tau protein that stabilizes MT, in previous research as well as experiments conducted in our study.
These results suggest that shifting the balance of neuronal microtubule regulation towards stabilization rather than destabilization without completely abolishing microtubule destabilization processes facilitates the maintenance of neuronal structure and promotes organismal longevity in C. elegans. The efa-6 loss-of-function mutants also maintained greater touch sensitivity and motor function during aging compared to wild-type worms. These differences in neuronal integrity and functional ability were time/aging-dependent with no significant differences between the efa-6 loss-of-function mutants and wild-type worms at day 1 of adulthood but significant differences between the groups by days 9 and 10 of adulthood. In addition, the expression of EFA-6 in neurons, but not in muscle, rescued the phenotypic changes seen in the loss-of-function mutants, suggesting that the regulation of microtubules within neurons is what contributes to the regulation of lifespan.