HOW NEURONS AFFECT LONGEVITY:

Ageing is characterised by the progressive decline in behavioural and cognitive functions. Functional imaging studies reveal a global loss of activity in many brain regions in aged human subjects (Andrews-Hanna et al., 2007; Bishop et al., 2010; Grady, 2012; Morrison and Baxter, 2012). Recent evidence suggests that, in most cortical regions of ageing brain, morphological and physiological changes at synapses, rather than neuronal loss, are the cellular basis of age-related alteration in connectivity and integrative function (Andrews-Hanna et al., 2007; Bishop et al., 2010; Grady, 2012; Morrison and Baxter, 2012).

Reduction of neurotransmitter signalling has been consistently observed in the ageing brain, although the extent of reduction varies among different neurotransmitters and across brain regions (Makman and Stefano, 1993). Both animal models and human studies (Wong et al., 1984; Rinne et al., 1990; Wang et al., 1998; Kaasinen et al., 2000; Ota et al., 2006; Kumakura et al., 2010) indicate a significant decline in dopamine synthesis and its receptor level in aged nervous systems. In the prefrontal cortex of humans and rhesus monkeys, there is an age-dependent down-regulation of genes involved in GABA transmission that could alter the balance between inhibitory and excitation neuro-transmission (Lu et al., 2004). Attenuation of serotonergic receptors has also been consistently reported in the ageing brain (Meltzer et al., 1998). Previous studies have established a correlation between dopamine decline and age-related behavioural alterations, including the changes in reward system and working memory (Braskie et al., 2008; Dreher et al., 2008). However, in long-lived animal models caused by food restriction and by gene mutations that result in decreased insulin signalling or mitochondrial function (Lin et al., 1997; Feng et al., 2001; Fontana et al., 2010; Kenyon, 2010), it is unknown whether there is alteration in neurotransmitter systems related to lifespan extension and whether such alteration affects behavioural deterioration.

The Caenorhabditis elegans nervous system uses an array of neurotransmitters, receptors, and downstream signalling mechanisms that are similar to those identified in the mammalian brain (Chase and Koelle, 2007). In this study, we found long-lived mutants with reduced insulin signalling or mitochondrial function showed similar age-dependent decline in 5-HT and DA level with that in wild-type N2 worms. Surprisingly, worms with dietary restriction (DR) showed no decline in 5-HT/DA level, and longevity regulator PHA-4 upregulated the synthesis of 5-HT/DA specifically in late adulthood of these DR worms. Furthermore, we found that elevation of endogenous 5-HT/DA helped to preserve several important behaviours, including slowing responses to food, pharyngeal pumping, and male mating, all of which showed deterioration in both aged wild-type and long-lived daf-2(e1370) animals. Thus, we have revealed that longevity genes differentially affect 5-HT/DA level and elevation of these transmitters could promote healthy behaviours in aging C. elegans.