Neurotrophic factors and longevity: an evolutionary view of the role of the brain in regulating lifespan

1. Introduction

Studies carried out in the last 25 years have shown that the theoretical maximal lifespan of a given species, 120 years for humans, is strongly correlated with its brain/body size ratio. This is particularly true in mammals, with the exception of bats which, on average, live three times longer than predicted by their brain and body size1. From these comparative anatomical studies the new concept has emerged, that lifespan is largely controlled by the brain. Evolutionary theories provide the key to understand how brain may control lifespan. According to this view, during evolution the control of the body metabolism (including control of energy storage in fat and active research for new energy, i.e. food), has been located in the brain which, as a consequence, has assumed the control of the entire body’s health and resistance to life stresses. On the other hand, the health of the brain itself is subjected to the general body’s health. Thus, it appears that the lifespan of an individual is determined by the mutual influence between brain and body involving a sort of two-ways return trip of ‘signals’ travelling from the body to the brain and back. Understanding how brain and body influence each other and what is the nature of these physiological signals will have a tremendous impact on our attitude towards life and ageing.

2. From body to brain

‘Mens sana in corpore sano’ (a sound mind in a sound body) is one of the most famous Latin quotation world wide from Decimus Iunius Iuvenalis, anglicised as Juvenal, a Roman satiric poet of the late 1st century and early 2nd century AD. Over time, the phrase has come to mean that only a healthy body can produce or sustain a healthy mind and it is certainly a common life experience for many people that physical exercise can have beneficial effects for both our physical and mental health. However, only recently, has extensive research on humans and animal models, provided evidence that exercise may have specific benefits on cognitive function, particularly in later life. Cognitive functions consist in the ability to elaborate information from the external and internal world acquired through the five senses (seeing, hearing, touching, smelling and tasting) and to give a meaning to these perceptions in order to produce a correct behavioural response to the environment. In humans, cognitive functions also include the so-called higher brain functions consisting in the ability to reason and to predict the consequences of our own and other people’s actions. Cognitive functions are particularly important as they allow us to adapt our actions and reactions to a changing environment, in a word, they allow us to learn.

Until the early 1990s, it was widely assumed that the beneficial aspects of physical exercise consisted in an unspecific action on general health that would also affect the brain health, albeit indirectly. However, when studies using animal models were directed towards understanding the neurobiological bases of these benefits, it turned out that exercise affects directly the molecular machinery of the brain itself. In these studies, voluntary wheel-running was selected because it allows rats or mice to choose how much to run (i.e. it avoids confounding variables associated with the stress of forced treadmill running and investigator handling) and it is quantifiable. It is now clear that voluntary exercise can increase levels of some proteins involved in the maintenance and repair of the brain such as the neurotrophin brain-derived neurotrophic factor (BDNF) and other neurotrophic factors2. BDNF, is a small protein that is secreted from neurons and belongs to the protein family of neurotrophins whose principal member is nerve growth factor (NGF). Through the discovery of NGF, the Nobel Prize laureates Rita Levi Montalcini and Stanley Cohen demonstrated for the first time that some proteins may have so-called neurotrophic properties, i.e. they can sustain the growth and survival of neurons. Accordingly, BDNF, like other neurotrophins, is able to stimulate genesis of new neuronal cells and increase resistance to brain insults by supporting the survival and growth of many neurons3,4. In addition, BDNF is unique in improving learning and mental performance because it acts as a key mediator of synaptic efficacy, neuronal connectivity and use-dependent plasticity5,6.
In their initial hypothesis, the researchers predicted that the response to exercise would probably be restricted to motor-sensory systems of the brain, such as the cerebellum, primary cortical areas or basal ganglia. The findings were surprising: several days of voluntary wheel-running increased levels of BDNF mRNA in the hippocampus7, a highly plastic structure of the brain that is normally associated with higher cognitive functions rather than motor activity. Theses effects appeared within days in both male8 and female9 rats were sustained even after several weeks of exercise10 and were paralleled by increased amounts of BDNF protein. In addition, running activity increased levels of BDNF mRNA in the lumbar spinal cord11, cerebellum and cerebral cortex8. Since learning, a high-order of brain plasticity, increases BDNF12, and BDNF, in turn, facilitates learning13 the prediction was that mechanisms that induce BDNF production, such as exercise, can enhance learning. Indeed, running enhances a form of long lasting memory called Long Term Potentation (LTP) and improves the ability of the animals to remember geographical landmarks to orient themselves14.
Recently, genomic analysis (high-density oligonucleotide microarray) has demonstrated that, in addition to increasing levels of BDNF, exercise mobilises expression of genes that are known to promote brain plasticity processes. However, although other trophic factors, including nerve growth factor (NGF)8 and fibroblast growth factor 2 (FGF-2), were also induced in the hippocampus in response to exercise, their increase was transient and less robust than that of BDNF, suggesting that BDNF is a better candidate for mediating the long-term benefits of exercise on the brain.
Thus, mild aerobic exercise such as for example walking, swimming or cycling provides a simple means to maintain brain function and promote brain plasticity by keeping high the brain levels of BDNF.

3. The return Way: from brain to body

There is no doubt that the nervous system controls large part of the normal functioning of our organs. In particular, most visceral functions (e.g. our digestion) are regulated by the autonomous nervous system, which controls automatically and without involving our will, large part of the internal organs’ physiology. However, only recently has the scientific community begun to accept the concept that the brain can actually control not only the general health status of one organism but even its lifespan. The first evidence came from studies showing that there is a strong positive correlation between brain size and maximum lifespan among mammalian species15,16. These studies demonstrated that animals having larger brains and relative smaller body size (i.e. high ‘brain/body-size’ ratio) live longer, with only one clear exception being that bats live considerably longer than mice of equal brain and body size17.
Why might the nervous system be a key regulator of lifespan? It could be argued that, since organisms without brains (e.g. yeast) have finite lifespan, the brain is not a fundamental determinant of lifespan. However, there is increasing evidence that brain can actually control lifespan. First of all, the nervous system can increase the probability of an organism of having a long lifespan simply by increasing its ability to escape mortal threats and have appropriate behavioural responses to specific environmental and social contexts. 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. On the other hand, the brain also controls neuroendocrine hormonal systems which are strongly implicated in ageing. Finally, according to a novel theory, during evolution the brain has acquired the ability to regulate energy metabolism throughout the body, and hence taken control of the molecular and biochemical processes that control ageing in brainless organisms. To better explain this theory, the role of the brain in regulating energy metabolism will now be analysed from an evolutionary perspective starting from the definition of what is ageing from an evolutionary point of view.

Enrico Tongiorgi: BRAIN Centre for Neuroscience, University of Trieste, Italy.
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