In summary, protein homeostasis appears to play a special role in the normal aging of neurons as well as in age-related neurodegenerative diseases, both of which are associated with the accumu- lation of diverse species of misfolded proteins in neurons. While this may be related to the lifespan of neurons themselves: for unknown reasons, the protein quality control mechanisms and stress- responses also appear to be attenuated in neurons when compared to other somatic tissue.
Recently, there is growing evidence that even when protein misfolding can be initiated locally in specific areas of the brain, it can spread through as yet unknown mechanisms to other unaffected parts of the nervous system. This could involve inflammation, the immune system, vasculature, or cell biological mechanisms such as exosome release and uptake. Neurons themselves appear par- ticularly susceptible to oxidative or protein misfolding stress that could result in a feed-forward loop triggering degeneration. The high energetic requirements of neurons also make them partic- ularly susceptible to mitochondrial dysfunction. Thus, even when pesticides such as rotenone or 6- OHDA which inhibit mitochondrial complex I function and trigger overactive ROS signaling are applied systemically to organisms they predominantly impact dopaminergic neurons, suggesting some inherent metabolic constraints that make these cells more susceptible to oxidative stress.
Mutations affecting mitochondrial function are linked with familial ALS and PD, and have been also associated with neuronal degeneration in AD patients. In addition, in mouse superoxide dis- mutase (SOD) mutant models of ALS hyperexcitability of neurons was already observed in neo- natal brains suggesting that the dysregulation of calcium and excitotoxicity may play a prominent role in neuronal death.173Structural changes in the brains of humans at advanced ages do not show consistent patterns of variation and MRI studies have only detected small changes in brain size with age. In addition, when neuronal cell loss has been reported it usually is in specific brain centers such as the hippocampus or locus coeruleus. Thus, gross neuronal and glial numbers seem to remain largely unchanged with age, and are not thought to be the main source of age-dependent decrease in functionality that typically accompanies aging. Thus the major mechanisms affecting neurons appears to be related to their long, postmitotic lifespan, their excitability, their interconnectedness and their energetic requirements and dependence on oxidative phosphorylation.
Despite these particular vulnerabilities of neuronal tissue, its age-related loss of integrity is very much tied into organismal function and is modulated by systemic factors. Indeed, while neurons themselves may or may not be privileged when it comes to the molecular mechanisms that destroy them, neuronal dysfunction could serve as a bottleneck, impacting the aging of all other tissue. In all organisms studied, the central nervous system plays a privileged role in orchestrating systemic aging. The somatotropic axis in mammals comprising the growth hormone (GH), and its second- ary mediator, insulin-like growth factor 1 (IGF-1), modulates energy utilization of all cells either directly or through secondary signaling cascades. Recent evidence shows that the nervous system also controls fundamental cellular responses to macromolecular damage, such as protein damage in remote cells. Similarly, the efferent vagus nerve-mediated cholinergic signaling controls immune function and proinflammatory responses of peripheral tissue via the inflammatory reflex. These control mechanisms appear to be modulatable switches that allow the organism to coordinate its metabolic responses, behavior, stress responses etc. to the availability of optimal conditions for growth and reproduction. However, dysregulation of any of these control mechanisms exerted by the nervous system could set off a systemic chain reaction that would lead to many of the phe- notypic changes seen during normal aging.
Among primates, humans appear uniquely vulnerable to many age-related neurodegenerative disorders.174However, human brains are distinguished also by a greater proportion of their cor- tical surface allocated to higher-order association cortex rather than primary sensory and motor areas. In addition, humans, but not primates, appear to have evolved a post-reproductive period175
52 Veena Prahlad and Madhusudana Rao Chikka
which, in recent generations has lengthened and spread across the globe to result in the upcoming
“silver tsunami.”The trade-off between reproduction and longevity is central to our evolutionary as well as molecular explanations of aging and decreasing fecundity, or postponing reproduction is linked to an extension in lifespan and better somatic health. Recently studies in a cohort of genet- ically and socially homogenous Ashkenazi Jewish centenarians with an average age of ~100 years showed that, as compared with an Ashkenazi cohort without exceptional longevity, the centenar- ians had fewer children (2.01 vs 2.53, p < 0.0001) and displayed a pattern of reproduction con- sistent with delayed reproductive maturity.176 Thus, how and whether the interplay between early fitness benefits such as fecundity and late-life somatic maintenance reflected by increased healthspan of humans is adaptive remains to be seen.
Key Readings
Gems, D, & Partridge, L. Genetics of longevity in model organisms: Debates and paradigm shifts.Ann. Rev.
Physiol., 75, 621–644 (2012). doi:10.1146/annurev-physiol-030212-183712
Kennedy, B. K., Berger, S. L., Brunet, A., Campisi, J., Cuervo, A. M., Epel, E. S.,…Sierra, F. Geroscience:
Linking aging to chronic disease.Cell, 159, 709–713 (2014). doi:10.1016/j.cell.2014.10.039
Deweerdt, S. Comparative biology: Looking for a master switch. Nature, 492, S10–S11 (2012).
doi:10.1038/492S10a
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58 Veena Prahlad and Madhusudana Rao Chikka