Caloric is the most consistent intervention to

Caloric restricted diet and cognitive abilities in aged animals

Anita Jagota, Muneesh Pal

We Will Write a Custom Essay Specifically
For You For Only $13.90/page!

order now

Neurobiology and Molecular Chronobiology Laboratory, Department of Animal Sciences,

School of Life Sciences, University of Hyderabad, Hyderabad 500046


ABSTRACT: To date, Caloric restriction (CR) is the most consistent intervention to prolong lifespan and prevent age-related disorders in various species from yeast to a rodent. Aging is the consequences of impairment in physiological and metabolic processes. Brain aging is a multi-factorial process that is occurring across multiple cognitive spheres. Learning and memory have been rescued in old age animals in different studies that are a consequence of aging by CR. Hippocampus is the very crucial part of the brain, involved in the spatial and explicit memory and learning. It has been studied that with aging, ROS and pro-inflammatory cytokines increase in the brain and other body tissues, which deplete DNA repair and maintenance and decreased autophagy. Moreover, other environmental factors also impart their effect on aging. CR increases the number of neurons and synaptic plasticity in the dentate gyrus in adult and old age animals, by enhancing the level of neurotrophic factors (BDNF and NF-3). There are several reports demonstrating, CR rats show better memory recollection in Morris Water Maze test as compared to normal rats. The dopamine and serotonin major neurotransmitters which play a crucial role in long-term potentiation (LTP) and as well as CREB activation, which directly involved in cognitive skills enhancement. CR has been reported to modulate the concentration of dopamine and serotonin. Neurogenesis occurs in the brain throughout life; however, this phenomenon is well documented in some specific brain areas as subventricular zone (SVZ) and subgranular zone (SGZ). The AMP-activated serine-threonine kinase (AMPK) and sirtuin (SIRT1) are two metabolic sensors which sense the concentration of AMP/ATP and NAD+/NADH level in cells respectively. SIRT1 regulates expression of different genes and AMPK phosphorylates different target proteins which ultimately increases cell survival and maintenance. This review concentrates on aging, a decline of cognitive abilities, major pathways related to memory enhancement with respect to CR intervention, Neurogenesis, and mechanism which sense the metabolites and transfer the effect of CR to the cells.


Keywords: Aging; Caloric Restriction; Cognitive abilities; Neurogenesis; LTPs




Aging is the normal and endogenous process in all animals and a principal risk factor for many among the major diseases and a key factor in the overall decline of behavioral, physical, and mental performance 1. Earlier, brain aging was considered as neuronal death in the hippocampus and related area and consequence of cognitive decline, but now this fact has been changed by the number of neurons do not change throughout the life2, 3. Thus, there is something else which leads to cognitive decline, maybe it is due to epigenetic changes. The regeneration ability of the brain and other tissue is decreased by results of aging 4. Now, the hippocampus is well known one of the brain areas who have the capacity of postnatal neurogenesis 4 however, neurodegeneration is the characteristic of Alzheimer’s disease. Caloric restriction is being used as therapeutics as well as a regime for experimental model invertebrates to mammals to extend the lifespan and, they have got success over the 100 years. Aged animals are showed decreased densities of neuropeptide Y (NPY) receptor subtypes in the hippocampus and dentate gyrus, cingulate cortex, thalamus, and hypothalamus that may have behavioral and physiological implications. A recent study has demonstrated that the medial thalamus represents an essential gateway allowing the acquisition and consolidation of short-term information as well as long-term nociceptive information processing, while anterior cingulate cortex is involved in nociceptive short-term information processing but not in long-term storage 5. Therefore Y1 receptor deficit in the hippocampus and cingulate cortex which contribute to the learning and memory decline 6. Long-term caloric restriction (LTCR) may protect neuropeptide Y receptor deficit and may allow protection of neural circuits involved in, feeding, memory pain and emotions functions 7. Synaptic efficiency, memory consolidation, and long-term synaptic plasticity are also increased when mice fed with long-term intermittent fasting diet (L-IFD) with respect to mice fed ad libitum 8. In Aging, Accumulation of pro-inflammatory and reactive oxygen species (ROS) leads to neurodegeneration due to mitochondrial dysfunction and abnormal metabolism. In the present article, we review how aging involved in cognitive decline and later we discuss its prevention or delaying a caloric restriction regimen.



Aging is the natural and universal occurring process, which has to be faced by every animal that was born in this mortal world. Aging is a progressive loss of physiological function that can lead to a variety of degenerative disorders, such as diabetes, cardiovascular disease, and Alzheimer’s disease. A myriad of hypotheses has been put forth to explain the causes of aging, including DNA damage, telomere shortening, mitochondrial dysfunction, hormonal imbalance, chronic inflammation, and cellular senescence in both the nervous system and other organ systems. Given the systemic nature of aging, the hypothalamus, a brain region that links neuroendocrine function to physiology, has drawn attention as a possible orchestrator of the overall physiological decline9 10.

Now, several kinds of research have been demonstrated that performance on most cognitive abilities decreases later in life. An  extensive number of well-powered studies and wide reviews of the literature have influentially demonstrated an age-related dampen in processing speed, working memory, as well as short- and long-term memory 11-13 Significantly, the effect of aging observed for specific tasks/cognitive domains have been found to transfer to more complex reasoning and general cognitive functioning 14, 15. Fascinatingly, while an age-related decline in cognitive performance has been constantly demonstrated in cross-sectional studies, some longitudinal studies have, at times, failed to confirm similar path 12.The mechanisms underlying age-related cognitive decline are not fully understood. While a “common cause” hypothesis of cognitive decline was initially proposed 16, such basic explanation is now thought to be unlikely 15. Indeed, neuroscientific research indicates that aging discernible non-uniformly across the brain 17-19) as well as across cognitive domains. For example, while the relatively linear decrease in performance from 20 to 80 years is valid to many cognitive domains 15, 20, it may not apply to diverse memory tasks for which performance was accounted to be relatively stable (or even increasing slightly) until mid-life and then decreasing into old age 14. Correspondingly, improving (or at least preserved) performance into older age has been reported for tasks relying on accrued knowledge and verbal capability 20, 21 It is also significance noting that the impact of aging on cognition is modified  by health issues (e.g., blood, anxiety, pressure) and lifestyle choices (e.g., exercise, diet) in a sex- and brain region-specific approach, and genetic variations will lead to supplementary age interactions due to their impact on the brain structure, cognitive abilities, vulnerability to neurodegeneration, and cognitive decline 21-28.


Brain plasticity is a primary prerequisite for the acquisition learning and storage memory of novel information, and a reduction of this capacity characterizes a most important hallmark of neurodegenerative disorders and of brain aging 29. Alterations in structure, number and function of synapses (synaptic plasticity), as well as generation of new neurons and their incorporation in pre-existing neural networks (adult neurogenesis) are major components of brain plasticity that are altered by metabolic and nutritional inputs. In rodents aging is supplemented by a decline in synaptic plasticity, as revealed by both biochemical (decline hippocampal long-term potentiation, LTP), and electrophysiological parameters. The latter include a declined expression of synaptic proteins (such as subunits of the NMDA-type and GABA-type glutamate receptor) as well as neurotrophin receptors (TrkB1) and neurotrophins (BDNF). Dietary restriction prevents these alterations, in corresponding with an improvement of cognitive function measured by hippocampus-dependent memory tasks 30, 31. Because synaptic plasticity and LTP significantly depend on mitochondrial activity at synaptic terminals 8, 30, 32 CR may enhance synaptogenesis and synapse potency, at least in part, by enhancing the mitochondrial integrity and bioenergetic efficiency. Fascinatingly LTP requires nitric oxide 33, a gaseous mediator that activates mitochondrial biogenesis in response to CR  34. An anti-inflammatory action of CR contributes to recover synaptic plasticity in the context of both brain acute brain damage and senescence35.



Neural stem cells (NSCs) are self-renewing cells that inhabit mainly in two regions in the subgranular zone (SGZ) of the dentate gyrus, and the ventricular-subventricular zone (V-SVZ), which lines the lateral ventricles. NSCs provide new neurons that are thought to add to brain plasticity, learning, memory, and repair. NSCs reproduce throughout life in both brain regions, however, as early as mid-age, NSC function declines to result in fewer proliferating cells and reduced neuronal output of NSCs. The murine V-SVZ turn into thinner during aging and displays a dramatic decline in proliferation and neurogenesis as measured using a 2-hour bromodeoxyuridine (BrdU) pulse and the number of doublecortin+ (DCX+) neuroblasts, respectively36. In vivo studies show the overall number of proliferating NSCs and progenitors plunge by 75% or more in aged rodents 36, 37 although a larger percentage of the remaining Type B NSCs are in a proliferative state in the aged V-SVZ compared to young mice38. Evidence suggests this is possible due to the lengthening of the cell cycle in activated Type B NSCs, specifically the G1 phase, as early as mid-adulthood, which serves to avoid further reduction of the aging NSC pool 39, 40. The V-SVZ niche also goes through age-associated structural modification wherein the lateral ventricle itself undergoes stenosis or merging of the V-SVZ with the nongerminal medial side of the ventricle 38. This results in an overall reduction in the size of the niche. Moreover, the V-SVZ vasculature undergoes remodeling during aging 36 and both vascular density, which was calculated by immunohistochemistry of endothelial cells, and blood flow, as measured by magnetic resonance imaging, are reduced in the aged respect to the young V-SVZ 41, which possible impacts the proliferative compartment of the V-SVZ. The microglial cells within the V-SVZ also exhibit dramatic changes during aging. Microglia usually functions as the innate immune cells in the brain. They play a role in both neuroinflammation and repair following brain insult 42. Inside the V-SVZ, microglia show an activated phagocytic state at mid-age that is escorted by increased proinflammatory cytokines IL-6, IL1- ?, and TNF? 43. Amusingly, inflammation related to brain aging, such as activated microglia, emerges much later in non-germinal regions, recommending that the VSVZ niche is exceptional in this middle age inflammatory phenotype 43. Purposely, the fate of a V-SVZ NSC is to incorporate as an interneuron into the olfactory bulb in rodents and sustain olfactory acuity 44. Due to the decline in Type BNSCs with age, fewer DCX + Type A neuroblasts are able to migrate to the olfactory bulb, resulting in a strikingly decline in new neurons incorporate into the olfactory tissue 7. The age-associated dampen in neurogenesis in the V-SVZ is observed behaviourally in aged rodents who exhibit olfactory insufficiency as measured using an olfactory memory test, which imitates the decrease in newborn neurons in the olfactory bulb 44, 45. Olfactory memory has been revealed to be specifically controlled by V-SVZ neurogenesis and is discrete from spatial learning and memory, which are interceded by hippocampal neurogenesis 44. Nevertheless, some studies have recommended that higher

order cognitive processing is dependent upon odor recognition and memory, and measurements of olfactory memory deficits might be a rodent correlate for human cognitive aging deficits 46.

Similar to the V-SVZ, the hippocampal neurogenic niche practices a non-linear decrease in neurogenesis with age 47, 48, with final numbers of in vivo proliferating progenitors about 75% lower at mid-age to aged (12-24 months) compared with young (2-month-old) mice 49. Conversely, the density of NSCs in the murine hippocampal subgranular zone remains comparatively stable throughout life, demonstrating that a quiescent Sox2-positive NSC pool remains accessible for activation 49. These rest NSCs give rise to interneurons that, though declined in number, retain a related level of structural complexity and spine density as their younger equivalents, and continue to form comparable levels of glutamatergic synapses within the existing hippocampal circuitry in vivo 50. The decline in the number of hippocampal progenitor cells is topographically discrete beside the dorso-ventral axis of the hippocampus, whereby the ventral dentate gyrus practices the most severe decline in NSCs by mid-age 51. This indicates a compromise in both spatial learning and memory (mediated by the dorsal horn) as well as emotional processing and anxiety (mediated by the ventral horn) 52. Condensed levels of neurogenesis are associated with deficits in hippocampal learning and spatial memory in aged rats as evaluated by the Morris water maze and visual pattern discrimination tasks 53, 54.



 Industrialization and advancement of medical science increased life expectancy has increased. Global life expectancy for both sexes increased from 65.3 years in 1990 to 71.5 years in 2013, and women made slightly greater gains than men.  Female life expectancy at birth has increased by 6.6 years and male life expectancy by 5.8 years. If trends seen over the past 23 years hold, by 2030 global female life expectancy will be 85.3 years and male life expectancy will be 78.1 years 55. With incensement of the life expectancy old disease also increase such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis, cognitive decline etc. Caloric restriction (CR) is an ancient aged intervention when Indian saints and yogis used to have fast for many weeks to months and they had a long healthy life. Now, as an advancement of science huge research has been done over the 100 years on experimental model invertebrates (C. eligans) to mammals (rat) and they concluded that CR increases longevity. CR by way of daily energy restriction or intermittent fasting is one likely intervention that may influence various aspects of the tyrosine kinase B (TrkB) signaling cascade in a fashion that may ultimately affect cognitive performance. Daily energy restriction in this area of research is typically characterized as a 20–40% reduction in caloric intake, without malnutrition 56. Intermittent fasting refers to abstention from energy intake for 16–24 hours and has similar general health benefits as compared to daily energy

Fig.1 Mechanisms underlying hippocampal aging and related cognitive decline. An increase in neuroinflammation, a decline in trophic factor, the occurrence of glutamate-mediated excitotoxicity and oxidative damage, as well as cellular senescence and aggregation of misfolded proteins, are all thought to give to age-related alteration in hippocampal circuitry and function. These changes weaken the regenerative and protective processes of this brain structure, leading to declining in structural and functional plasticity (i.e., a reduction in neurogenesis, dendritic arborization, and synaptic plasticity) and an increase in apoptosis. As a result of neuronal loss and neuroplasticity reduction, aged animals and elderly individuals may present a decline in hippocampal volume, which is thought to be related with deficits in hippocampal-dependent learning and memory and an increased susceptibility to certain neurological conditions related with cognitive destruction. Abbreviations: FGF-2, fibroblast growth factor-2; SASP, senescence-associated secretory phenotype BDNF, brain-derived neurotrophic factor; VEGF, vascular endothelial growth factor IGF-1, insulin growth factor-11


restriction 57. It has also been noted that CR can delay age-related declines in learning, spatial and working memory, and neurotrophic factor expression in the hippocampus with evidence that this mediated through the TrkB signaling cascade 58-60.

            Especially, CR can positively persuade expression of hippocampal brain-derived neurotrophic factor (BDNF) 61, phosphorylation of cAMP response element binding protein (CREB) 62, dendritic spine density 63, and transcription of BDNF 64. Influential work has been done in this field provided novel evidence for an increase in BDNF expression and transcription through intermittent fasting 65. The better expression of hippocampal BDNF and increases in dendritic spine density were also found after three months of 40% CR 63. However, not assessed in these particular studies, previous mechanistic work supports increased BDNF and dendritic spine density leading to the recovered performance on hippocampal-related cognitive tasks such as learning and memory 61.




CR as an intervention is possible to be very difficult to implement in humans. Consecutively to gain the beneficial effects of CR without the restriction of calories, a number of nutraceuticals and established drugs are being investigated as a means to mimic the effects of CR. So far numerous effective compounds have been identified some of which have been used in human clinical applications such as rapamycin (inhibitor of mTOR), metformin (activator of AMPK), and others that are only recently being applied in human studies such as resveratrol (activator of AMPK and SIRT1). The factor that is responsible for

Fig. 2. Metabolic regulation of histone acetylation by fasting/CR in neurons. Ketone s bodies are serving energy substrates for neurons during fasting also act as epigenetic modulators by inhibiting Class I histone deacetylases and increasing the extramitochondrial pool of acetyl-CoA available for histone acetylation by the HAT. Sirt1 modulate to the acetyl-CoA pool by deacetylating/activating the cytosolic enzyme acetyl-CoA synthase 1. Fasting-induced epigenetic modulators also include NO that inhibits HDACs downstream of BDNF-nNOS-CREB-signaling. Direct histone deacetylation by Sirt1 (that releases O-acetyl-ADP-ribose) also participates in this epigenetic circuitry. Abbreviations: transferases; HAT, histone acetyl HDAC; histone deacetylases; NOS, NO synthase; ACS, acetyl-CoA synthase; OAADPr, O-acetyl-ADP-ribose 66

the metabolic effects of resveratrol is a point of debate, both AMPK and SIRT1 have been recommended to be the target of resveratrol 67, 68 and this has been the primary encouragement to pursue its abilities as a CR mimetic 69. Resveratrol has been shown to extend lifespan in metabolically negotiated mice 70. Rapamycin treatment causes inhibition of TORC I and has been revealed to extend lifespan in a various number of species including yeast, worms, flies, and more recently mice 71. AMPK is considered as a key sensor and effector72 slight is known about the role of AMPK in the neuroprotection of CR. A study has shown that CR diet improved learning and memory of C57/BL mice, which is accompanied by increased AMPK and GLUT4 protein and mRNA expression in the hippocampus. They speculate AMPK pathway might play a role in cognitive performance. Nevertheless, the mechanisms of the effects of CR on memory are a controversial issue. Thus, it is of great importance to understand the crosstalk between various signaling pathways in the brain under CR circumstances. They confirmed their hypothesis that AMPK pathway is involved in the neuroprotection of CR. Moreover, there is a hypothetical mechanism for various neuronal signaling pathways in the neuroprotection of CR (Fig .2) 73 CR can improve learning and memory, and mice fed a CR diet demonstrate upregulation of SIRT1 expression and downregulation of mTOR and S6K1 activation 74. SIRT1is found in many brain regions and is 75 an important regulator of metabolic processes under normal and calorie-restricted conditions76, 77. SIRT1 proteins are very sensitive to the caloric discrepancy and are thought to intervene the beneficial effects of CR 78; although, the mechanism underlying SIRT1 activation by CR remains unclear. Upregulated SIRT1 can activate the Notch signaling pathway and inhibit mTOR signaling; equally, SIRT1 deficiency consequences in elevated mTOR signaling74, 79 80.


Fig. 3 A hypothetical mechanism for neuronal SIRT1/AMPK pathway and PI3K/Akt pathway in the neuroprotection of CR. Improved spatial learning ability of mice fed with the CR diet was regulated probably by the activation SIRT1/AMPK pathway and suppression PI3K/Akt pathway in the hippocampus, and mTOR mediated autophagy was also involved 73


CR can induce SIRT1by increasing the NAD+/NADH ratio, and thus control cell proliferation and differentiation, degradation, apoptosis and protein synthesis, aging inflammation and other physiological processes, and activate mTOR-mediated autophagy. SIRT1 can also directly activation of autophagy by the deacetylation of autophagy proteins such as Atg5, Atg7, and Atg8 81.




           To date, huge research has been done on CR and its impact on aging and associated impairments also revealed. CR delay and preserve cognitive decline which mediated by several pathways (mTOR, SIRT1/AMPK, and PI3K/Akt) and mediators or sensors. CR is directly involved in postnatal hippocampus neurogenesis, synaptogenesis and synaptic plasticity which ultimately responsible for learning and memory. Now CR or dietary restriction may be used as therapeutics for cognitive impairments.




How does CR increase hippocampus neurogenesis, synaptogenesis, and synaptic plasticity yet to be known?