There is generally a positive correlation between brain/body size ratio and lifespan, particularly among mammals, suggesting a role for the brain in determining lifespan.
Recent studies in diverse organisms including nematodes, flies and rodents have provided evidence that, indeed the brain may control lifespan.
Signaling pathways involved in both central nervous system and peripheral stress responses and regulation of energy metabolism may play important roles in lifespan determination.
Why might the nervous system be a key regulator of lifespan? It could be argued that, because, organisms without brains (e.g. yeast) have finite life spans, the brain is not a fundamental determinant of lifespan.
However, as the brain evolved it may have, through its ability to regulate cell signaling and energy metabolism throughout the body, taken control of the molecular and biochemical processes that control aging in brainless organisms.
There is a strong positive correlation between brain size and maximum lifespan among mammalian species with only one clear exception being that bats live considerably longer than mice of equal brain and body size.
The brain also controls neuroendocrine systems strongly implicated in aging.
The hypothalamic-pituitary system has a strong influence on lifespan as indicated by the increased life spans of Snell and Ames dwarf mice which have mutations that result in underdevelopment of the pituitary gland.
One pituitary hormone that may control lifespan is growth hormone, because, mice with deficits in growth hormone production have an increased lifespan.
Neural cells in the hypothalamus are controlled by the brain, but also by circulating factors such as leptin that may provide feedback as to the state of the bodies' energy metabolism. In this way the brain coordinates energy status with feeding behaviors.
A consistent feature of environmental and genetic factors that increase longevity is that they increase cellular resistance to stress.
Most types of stressors are first perceived by the nervous system (seeing a mugger in a dark alley, hearing a growling tiger, or feeling the pain from an injury).
The brain coordinates the responses of the whole body to such stressors on both rapid and long-term time scales by modulating the activities of neuroendocrine pathways (involving the hypothalamus and pituitary gland) and the autonomic nervous system.
The responses typically involve a behavioral response (fleeing the mugger or tiger), a vascular response (increased blood pressure and diversion of blood flow from the gut to muscles) and a metabolic response (increased mobilization of glucose).
An increased ability of an organism to escape from a potentially lethal stressor will obviously increase its probability of having a long lifespan, and this is one way the brain can determine average lifespan.
In the case of humans, intelligence is associated with a longer average lifespan by virtue of implementation of knowledge on how to prevent and treat various diseases.
However, the brain may also control maximum lifespan by its ability to stimulate signaling pathways that increase the resistance of cells to stress.
For example, upregulation of the expression of antioxidant enzymes such as Mn-SOD and Cu/Zn-SOD, and protein chaperones such as HSP-70, can increase lifespan in Drosophila. Interestingly, neuron-specific upregulation of Cu/Zn-SOD also extends lifespan in Drosophila.
N-acetylserotonin (a melatonin precursor) and melatonin (given intra peritoneum for 4 weeks) increased antioxidant capacity of the brain as demonstrated by decreased levels of malondialde-hyde and 4-hydroxynonenal and increased cellular glutathione peroxidase (Gpx) levels in the brains of male mice, and both of these compounds administered with drinking water prolonged lifespan by 20% compared with controls.
The neurotransmitter serotonin (5-HT) is converted to melatonin in the pineal gland and so may be involved indirectly in the antioxidant effects and may influence longevity by this mechanism.
Indeed, genetic and environmental manipulations of these systems can greatly affect lifespan by changing levels of hormones that modulate energy metabolism, stress resistance and regenerative capacity of cells throughout the body.