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Abstract
T
he animal’s ability to maintain homeostasis in response to different environments can
influence its survival. This chapter will discuss the mechanisms by which environmental
cues act through sensory pathways to influence hormone secretion and homeostasis.
Interestingly, recent studies also show that there is a sensory influence on lifespan that requires
the modulation of hormonal signaling activities. Thus, this raises the possibility that the sensory
influence on homeostasis underlies the sensory influence on lifespan.
Introduction
To optimize survival, animals must maintain relative constancy within their internal environ‑
ment, also known as homeostasis, by adjusting their physiology in response to their changing
external environment. Thus, animals employ many mechanisms to: (1) define set points at which
different physiological processes function most efficiently under given conditions; and (2) prevent
large deviations from these defined set points.
Internal vs. External Sensors
Specification of these set points, such as blood glucose levels, is subject to internal and external
stimuli that are detected by different types of sensors. The sensors that detect internal stimuli typi‑
cally monitor quantitative differences between set points and the existing internal environment.
Since many of these internal sensors are involved in transmitting signals through negative feedback
systems that correct deviations back to predetermined set points, these homeostatic sensors are
required to function with a high level of precision.1,2 An example of a homeostatic internal sensor
is the enzyme glucokinase in the pancreatic β cell, which is a sensor for internal glucose levels to
control ATP concentrations and thus insulin secretion from pancreatic β cells.2,3 The mechanisms
by which internal sensors regulate animal homeostasis will not be discussed further here and are
reviewed elsewhere.2,4‑6 Rather, this chapter will focus on the role of external cues and their sensors
in influencing homeostasis by modulating defined set points.
The sensors that detect external stimuli generally play a more important role in assessing qualita‑
tive differences between various external environments.7,8 Accordingly, external sensors can function
with a relatively lower degree of precision to perceive a wider range of concentrations of specific
stimuli.7,8 Indeed, such external sensors are less likely involved in rectifying fluctuations from set
points but are more likely involved in modulating or resetting the set points.
This chapter will discuss (1) how external sensory inputs are recognized and transduced by their
respective sensory cells; and (2) how such sensory information is further processed to modulate
the secretion of peptide hormones that maintain homeostasis by regulating different physiological
processes. Since external sensory cues and the sensory system have recently been shown to influence
lifespan,9‑11 this chapter will also address possible mechanisms involved in the sensory influence
on aging, which includes progressive impairment of animal homeostasis.
Figure 1. A regulatory motif for the sensory influence on homeostasis. A) Sensory neurons
convert various cues to neural activity. Sensory neuron activity is propagated through neural
circuits, where information processing and transmission occurs via inter‑ and intracellular
signals. Ultimately, the neural circuits signal to neuroendocrine cells or endocrine organs,
which lead to the release of hormones that alter the physiological state of the animal. Multiple
regulatory motifs may be combined into a signaling network, allowing cross‑talk between
physiological and sensory processes117. B) A schematic diagram showing the molecular nature
of sensory transduction pathways that lead to neurotransmitter or hormone release. C) A
scheme demonstrating the flow of sensory information that leads to the secretion of hormones
that regulate homeostasis. In some cases, the activated sensory neuron releases the hormone
itself through an intracellular signaling cascade, like the one depicted in panel B.
200 Protein Metabolism and Homeostasis in Aging
cues in contrast to gustatory cues are also only beginning to be elucidated. For example, the map of
postsynaptic partners of gustatory and olfactory neurons shows considerable overlap.76 However,
olfactory neurons synapse more extensively onto one set of interneurons, whereas gustatory neurons
synapse more onto another set of neurons.76
Fruitflies: In Drosophila, the neurons that detect gustatory and olfactory stimuli are found in
anatomically different structures.77 Taste inputs are communicated either directly or indirectly to
the subesophageal ganglion (SOG), which further relays taste information not only to higher brain
centers, the ventral nerve cord and nonneuronal tissues but also to neuroendocrine cells.77,78 This
raises the possibility that gustatory cues can also modulate the release of hormones that regulate
fly homeostasis. Interestingly, a small cluster of SOG neurons that express the neuropeptide hugin,
of this neural circuitry, olfactory cues have also been shown to stimulate the secretion of LHRH,
which not only controls the release of other hormones required for gonadal development and
function but may also directly promote mating behavior.90,91
Thus, together these gustatory and olfactory circuits can allow the hypothalamus to integrate
both external and internal sensory information to control animal homeostasis in response to the
changing quality of the environment.
Figure 2. Specific gustatory and olfactory neurons influence C. elegans lifespan through hormonal ©2010 Copyright Landes Bioscience. Not for Distribution.
signaling pathways. A) Certain gustatory neurons (ASI, ASG) shorten lifespan, whereas other
neurons (ASJ, ASK) lengthen lifespan. Both classes of gustatory neurons appear to modu‑
late insulin/IGF‑1 signaling to affect worm lifespan. B) A schematic diagram of the worm’s
gonad precursor cells showing that the germline cells (GC, gray circles) inhibit longevity in a
daf‑16‑dependent manner. On the other hand, the somatic gonad (SG, white circles) promotes
longevity in an olfactory neuron‑dependent and daf‑2‑dependent manner.
is expressed in a pair of olfactory neurons.102 So far, it is unclear whether olfactory neurons release
a signal that modulates DAF‑2 activity or whether DAF‑2 blocks the release of a signal from the
olfactory neurons to inhibit longevity.
The olfactory influence on lifespan has also been reported in Drosophila.11 Flies that lack the
atypical olfactory receptor Or83b, which is required for the proper subcellular localization of many
of the olfactory receptors,103 not only have severe olfactory deficits but also live long.11 Conversely,
olfaction has been shown to shorten the lifespan of dietary‑restricted flies.11
Dietary restriction (DR) is a treatment that can extend the lifespan of many species, ranging from
yeast to mammals.92,104‑106 DR, by its very nature, indicates a role for the environment in influencing
lifespan. Since the lifespan increase seen in dietary‑restricted flies can be partly suppressed when
the flies are exposed to food‑associated odors alone,11 it appears that sensory perception itself can
trigger a physiological change that can antagonize the DR response. In long‑lived Or83b mutant
206 Protein Metabolism and Homeostasis in Aging
flies, the mRNA levels of most of the insulin‑like genes are not significantly downregulated, with
the exception of one member of this family.11,107 Since the insulin pathway has also been shown to
affect fly lifespan,108‑112 it is possible that the change in expression of one of the insulin‑like genes
mediates the olfaction‑induced physiological change that affects lifespan. Although the mechanism
behind this sensory influence on lifespan currently remains unknown, it is not surprising that the
olfactory system, which can signal the levels or quality of food in the environment, would mediate,
at least in part, the effects of DR on lifespan extension.
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