Multiple factors are implicated in age-related physical brain changes and normal decline of memory and brain functioning. Continuing research is clarifying the relationships among these factors with new insights coming into focus. I report here on some of those relationships as well as interventions that can avert or even possibly reverse age-related cognitive or memory decline. This blog entry particularly deals with what is going on in the aging hippocampus and links up a number of topics I have discussed previously in this blog and in my longevity treatise – neurogenesis, BDNF, exercise, resveratrol, and curcumin.
About the hippocampus and aging
“The hippocampus is a major component of the brains of humans and other mammals. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Like the cerebral cortex, with which it is closely associated, it is a paired structure, with mirror-image halves in the left and right sides of the brain. In humans and other primates, the hippocampus is located inside the medial temporal lobe, beneath the cortical surface. It contains two main interlocking parts: Ammon’s horn and the dentate gyrus. — Since different neuronal cell types are neatly organized into layers in the hippocampus, it has frequently been used as a model system for studying neurophysiology. The form of neural plasticity known as long-term potentiation (LTP) was first discovered to occur in the hippocampus and has often been studied in this structure. LTP is widely believed to be one of the main neural mechanisms by which memory is stored in the brain. (ref).”
Brain cell renewal depends on neurogenesis due to differentiation of neural stem cells mainly in the hippocampus and cell migration. The process goes on throughout life.
The rate of neurogenesis tends to decline with aging and maintenance of an adequate level of neurogenesis is another important consideration in keeping an aging brain vital.
From the August 2010 blog post Neurogenesis, curcumin and longevity: “An introductory discussion of neurogenesis can be found in my treatise in the section on the Neurological degeneration theory of aging. “Increasing research evidence suggests that maintaining a sufficient and consistent rate of neurogenesis in the brain, particularly in the hippocampus, is important for the maintenance of cognitive health. Insufficient or irregular neurogenesis is thought to be a causative factor in bipolar disease and other mood disorders. Neurogenesis takes place throughout the life of a mammal in two major brain structures: the dentate gyrus of the hippocampus and the subventricular zone of the forebrain. In these regions neural progenitor cells continuously divide and give birth to new neurons and glial cells. In the mammalian brain neural progenitor cells are multipotent. They can differentiate into neurons, astrocytes or oligodendrocytes, though the factors that determine differentiation are poorly understood. The rate of neurogenesis tends to decline with advancing age in old mammals, as well as the does the number of functional neurons.”
The 2009 publication Endogenous regulation of neural stem cells in the adult mammalian brain relates: “Tissue-specific stem cells replenish organs by replacing cells lost due to tears and wears or injury throughout life. Long considered as an exception to this rule, the adult mammalian brain has consistently been found to possess stem cells that ensure neurogenesis. Neural stem cells persist within the subventricular zone bordering the lateral ventricles of the brain. Constitutively, neural stem cells proliferate and produce a continuous supply of new neurons that migrate towards the olfactory bulb where they ensure turnover of interneurons. Owing to their potential clinical use for the treatment of neurodegenerative diseases, the factors that control proliferation, self-renewal and differentiation of neural stem cells have received increasing interest. These studies have unraveled that the cellular dynamic within the subventricular zone is tightly controlled by astrocytes and endothelial cells that neighbor neural stem cells. These neighboring cells produce substrate-bound and soluble factors that make up a specialized microenvironment named the neurogenic niche. The equilibrium between neural stem cells activity and quiescence is adjusted by neurons located in remote brain areas that adapt neuron production to physiological and pathological constraints. Brain injury or neurodegenerative diseases affect neural stem cells proliferation, differentiation and migration suggesting that neural stem cells are involved in brain self-repair. Understanding the endogenous mechanisms that regulate neural stem cells will help to replenish cellular constituents lost by injury and thereby allow an effective development of neural stem cells based therapies of brain diseases.”
The 2009 publication Cell migration in the normal and pathological postnatal mammalian brain relates “In the developing brain, cell migration is a crucial process for structural organization, and is therefore highly regulated to allow the correct formation of complex networks, wiring neurons, and glia. In the early postnatal brain, late developmental processes such as the production and migration of astrocyte and oligodendrocyte progenitors still occur. Although the brain is completely formed and structured few weeks after birth, it maintains a degree of plasticity throughout life, including axonal remodeling, synaptogenesis, but also neural cell birth, migration and integration. The subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus are the two main neurogenic niches in the adult brain. Neural stem cells reside in these structures and produce progenitors that migrate toward their ultimate location: the olfactory bulb and granular cell layer of the DG respectively. The aim of this review is to synthesize the increasing information concerning the organization, regulation and function of cell migration in a mature brain. In a normal brain, proteins involved in cell-cell or cell-matrix interactions together with secreted proteins acting as chemoattractant or chemorepellant play key roles in the regulation of neural progenitor cell migration. In addition, recent data suggest that gliomas arise from the transformation of neural stem cells or progenitor cells and that glioma cell infiltration recapitulates key aspects of glial progenitor migration. Thus, we will consider glioma migration in the context of progenitor migration. Finally, many observations show that brain lesions and neurological diseases trigger neural stem/progenitor cell activation and migration toward altered structures. The factors involved in such cell migration/recruitment are just beginning to be understood. Inflammation which has long been considered as thoroughly disastrous for brain repair is now known to produce some positive effects on stem/progenitor cell recruitment via the regulation of growth factor signaling and the secretion of a number of chemoattractant cytokines. This knowledge is crucial for the development of new therapeutic strategies. One of these strategies could consist in increasing the mobilization of endogenous progenitor cells that could replace lost cells and improve functional recovery.”
The April 2011 publication Adult Neural Stem Cells: Response to Stroke Injury and Potential for Therapeutic Applications reports “The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection.”
With aging there is normally a decline in the volume of the hippocampus along with a decline in memory and brain processing capability. However, such declines appear not to be universal and may be averted.
The 2010 publication Involvement of BDNF in age-dependent alterations in the hippocampus reports.”It is known since a long time that the hippocampus is sensitive to aging. Thus, there is a reduction in the hippocampal volume during aging. This age-related volume reduction is paralleled by behavioral and functional deficits in hippocampus-dependent learning and memory tasks. This age-related volume reduction of the hippocampus is not a consequence of an age-related loss of hippocampal neurons. The morphological changes associated with aging include reductions in the branching pattern of dendrites, as well as reductions in spine densities, reductions in the densities of fibers projecting into the hippocampus as well as declines in the rate of neurogenesis.”
Brain-derived neurotrophic factor (BDNF) is a factor critically involved in the regulation of age-related processes in the hippocampus including loss of hippocampal volume.
The previously-mentioned publication reports “In this review it is hypothesized that brain-derived neurotrophic factor (BDNF) is a factor critically involved in the regulation of age-related processes in the hippocampus. Moreover, evidences suggest that disturbances in the BDNF-system also affect hippocampal dysfunctions, as e.g. seen in major depression or in Alzheimer disease.” For background on BDNF see my March 2010 blog entry BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting. That blog entry discusses BDNF in relationship to dementia, mental balance, aging, mental exercise and epigenetics.
The 2010 publication Brain-derived neurotrophic factor is associated with age-related decline in hippocampal volume relates “Hippocampal volume shrinks in late adulthood, but the neuromolecular factors that trigger hippocampal decay in aging humans remains a matter of speculation. In rodents, brain-derived neurotrophic factor (BDNF) promotes the growth and proliferation of cells in the hippocampus and is important in long-term potentiation and memory formation. In humans, circulating levels of BDNF decline with advancing age, and a genetic polymorphism for BDNF has been related to gray matter volume loss in old age. In this study, we tested whether age-related reductions in serum levels of BDNF would be related to shrinkage of the hippocampus and memory deficits in older adults. Hippocampal volume was acquired by automated segmentation of magnetic resonance images in 142 older adults without dementia. The caudate nucleus was also segmented and examined in relation to levels of serum BDNF. Spatial memory was tested using a paradigm in which memory load was parametrically increased. We found that increasing age was associated with smaller hippocampal volumes, reduced levels of serum BDNF, and poorer memory performance. Lower levels of BDNF were associated with smaller hippocampi and poorer memory, even when controlling for the variation related to age. In an exploratory mediation analysis, hippocampal volume mediated the age-related decline in spatial memory and BDNF mediated the age-related decline in hippocampal volume. Caudate nucleus volume was unrelated to BDNF levels or spatial memory performance. Our results identify serum BDNF as a significant factor related to hippocampal shrinkage and memory decline in late adulthood.”
“Changes in the concentration of brain-derived neurotrophic factor (BDNF) might be contributing to shrinkage of the hippocampus in late adulthood. BDNF, a molecule that is highly concentrated in the hippocampus (Murer et al., 2001; Phillips et al., 1990; Wetmore et al., 1990), is important in synaptic plasticity (Figurov et al., 1996; Kang & Schuman, 1995; Pang et al., 2004; Stoop & Poo, 1996; Tanaka et al., 2008) and is thought to contribute to neurogenesis in the dentate gyrus (Benraiss et al., 2001; Pencea et al., 2001; Takahashi et al., 1999), but its concentration declines in late adulthood (Lommatzsch et al., 2005; Ziegenhorn et al., 2007, however see Lapchak et al., 1993). Smaller hippocampal volumes predict more rapid conversion to dementia (Grundman et al., 2002) and poorer memory function (Erickson et al., 2009) (ref).”
Polymorphisms in the BDNF gene can be associated with mental disorders and such changes can also affect hippocampus volume
The above-mentioned blog entry discusses how the Val66Met polymorphism of the BDNF gene can affect mental states and dementia.
“In humans, a single nucleotide polymorphism in the BDNF gene affects the regulated secretion of BDNF in the hippocampus (Egan et al., 2003) and has been related to lower serum levels of BDNF (Ozan et al., 2010) and smaller hippocampal volumes (Bueller et al., 2006; Pezawas et al., 2004; Szeszko et al., 2005)—RESULTS Hippocampal, but not caudate nucleus volume, declines with increasing age. Consistent with prior research (e.g. Raz et al., 2005), hippocampal volume declined with advancing age after adjusting for total intracranial volume and sex. — Spatial memory performance declines with increasing age — Larger hippocampal volumes were positively associated with spatial memory performance — BDNF is positively related to spatial memory performance — we found that increasing age was associated with reduced levels of BDNF, and reduced levels of BDNF were related to both decline in hippocampal volume and elevated memory deficits. — Interestingly, the mediation results of the hippocampus on age-related memory decline were relatively specific to the left hippocampus, and not to the right. Other studies have reported asymmetries in the volume and function of the left and right hippocampus (Erickson et al., 2009) and suggest that the left and right hemispheres might play different, but complementary roles, in memory tasks that emphasize speed. Our results suggest that the left hippocampus is related to measures of speed for all memory set sizes, and the right hippocampus only for the 3-item condition(ref).”
Exercise causes upregulated expression of BDNF leading to increase in hippocampus size and memory improvement
The 2011 publication Exercise training increases size of hippocampus and improves memory reports “The hippocampus shrinks in late adulthood, leading to impaired memory and increased risk for dementia. Hippocampal and medial temporal lobe volumes are larger in higher-fit adults, and physical activity training increases hippocampal perfusion, but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown. Here we show, in a randomized controlled trial with 120 older adults, that aerobic exercise training increases the size of the anterior hippocampus, leading to improvements in spatial memory. Exercise training increased hippocampal volume by 2%, effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF, a mediator of neurogenesis in the dentate gyrus. Hippocampal volume declined in the control group, but higher preintervention fitness partially attenuated the decline, suggesting that fitness protects against volume loss. Caudate nucleus and thalamus volumes were unaffected by the intervention. These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood, which is accompanied by improved memory function.” The effect is not a large one but is still significant.”
One mechanism that may be involved in increasing brain volume through exercise may be the increased expression of BDNF brought about by exercise. The positive effect of exercise on BDNF expression has been noted for some time, for example in the 2002 publication Voluntary Exercise Induces a BDNF-Mediated Mechanism That Promotes Neuroplasticity. Another is Endurance training enhances BDNF release from the human brain.
In the recent blog entry PQQ – activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis I discussed how the supplement substance PQQ encourages mitochondrial biogenesis emulating exercise in that regard, and is neuroprotective. PQQ works via mitochondria by upregulating expression of the PGC-1alpha gene and expression of the SIRT3 gene. I looked hard at the literature to see what I could find out about interaction of the BDNF and PGC-1alpha/SIRT3 exercise-related pathways. I discovered little, however, and it appears that the pathways probably function independently but possibly synergistically.
The blog post BDNF gene – personality, mental balance, dementia, aging and epigenomic imprinting point out how mental exercise also stimulates expression of BDNF and longevity. See too the blog posts Mental exercise and dementia in the news again and Brain fitness, Google and comprehending longevity .
Cognitive and memory decline with age is not inevitable and can be influenced by many factors including diet and exercise.
Maintaining neuronal and cognitive plasticity is important for averting age-related memory decline and cognitive aging.
The November 2010 publication Neuronal and Cognitive Plasticity: A Neurocognitive Framework for Ameliorating Cognitive Aging relates: “Neuronal plasticity (e.g., neurogenesis, synaptogenesis, cortical re-organization) refers to neuron-level changes that can be stimulated by experience. Cognitive plasticity (e.g., increased dependence on executive function) refers to adaptive changes in patterns of cognition related to brain activity. We hypothesize that successful cognitive aging requires interactions between these two forms of plasticity. Mechanisms of neural plasticity underpin cognitive plasticity and in turn, neural plasticity is stimulated by cognitive plasticity. We examine support for this hypothesis by considering evidence that neural plasticity is stimulated by learning and novelty and enhanced by both dietary manipulations (low-fat, dietary restriction) and aerobic exercise. We also examine evidence that cognitive plasticity is affected by education and training. — Across a range of species – rats, monkeys, and humans – a sizeable subset of older individuals do not succumb to cognitive or brain decline (Willis and Schaie, 1986; Rapp and Amaral, 1991; Gallagher et al., 1993; Lee et al., 1994; Glisky et al., 2001). Moreover, even in old age the brain remains capable of plasticity – ability to change neurons and networks in response to experience (Kleim et al., 2003). The apparent persistence of plasticity late in life may provide some protection against age-related cognitive decline.”
The relationship between age-related brain shrinkage and cognitive capability is not clear
Continuing from the same publication: “The neural substrate of cognitive aging is not understood. Although cortical shrinkage occurs with age, such shrinkage is unrelated to cognitive change. Several research groups have attempted to relate regional cortical shrinkage to longitudinal cognitive change and found either an inverse relation or no relation (Rodrigue and Raz, 2004; Van Petten, 2004; Van Petten et al., 2004). Looking longitudinally over 5 years, shrinkage in neither hippocampus nor prefrontal cortex was related to cognitive change over the same period. Only shrinkage in entorhinal cortex, known to be the initial site of pathology of AD, was related to memory change (Rodrigue and Raz, 2004). Similarly, neuron loss in aging is minimal. Although for many years, age-related neuron loss was reported, the use of newer, un-biased, stereological techniques for counting neurons revealed no significant neuron loss in old age (reviewed in (Morrison and Hof, 1997). Although cross-sectional studies show near linear decline in many cognitive functions from young to old adulthood (Park et al., 2002), white matter actually increases over the same age range (Bartzokis, 2004). Synapse loss occurs only late in life after age 65 or so (reviewed in Masliah et al., 2006) and is reversible (reviewed in Greenwood, 2007). Effects of aging on biophysical properties of neurons are selective and subtle, seen only in specific brain regions and cell types (Burke and Barnes, 2006). Dopamine neurotransmission has been found to influence working memory performance, in a way that varies with age but also varies with cognitive performance regardless of age (Volkow et al., 1998; Backman et al., 2000). Thus, the substrate of cognitive aging is not known. One source of the difficulty in relating brain structure to cognitive change in old age may be the brain’s ability to adapt. In light of evidence that plastic changes leading to improved function after training can occur even following stroke (Taub et al., 2002; Ro et al., 2006), plastic changes may be ongoing, even in the face of cortical shrinkage and white matter damage. As reviewed below, there is evidence for such adaptation in old age in the heightened activation of cortical regions supporting executive resources, claimed to occur as compensation (Grady, 1996; Grady et al., 2005; Wingfield and Grossman, 2006).”
Exercise enhances neurogenesis and synaptic plasticity
Continuing: “ Animal work has consistently shown that physical exercise increases proliferation and survival of new neurons in the dentate gyrus of the hippocampus of adults (Gould et al., 1999; van Praag et al., 1999; Lou et al., 2008; Naylor et al., 2008). Rodents given access to a running wheel typically voluntarily run as much as 3–8 km per night and this is associated with a doubling or tripling of the number of newborn cells in the subventricular zone of the dentate gyrus where neurogenesis occurs. Voluntary wheel running over long periods of time is also associated with an increase in survival of later-stage progenitor cells and newly-formed (early post-mitotic) neurons in mouse dentate gyrus (Kronenberg et al., 2006). After experimental stroke, voluntary running enhanced progenitor cell survival in dentate gyrus in mice (Luo et al., 2007). This effect may extend beyond the hippocampus, as running rats also showed significantly higher number of cholinergic neurons in the diagonal band of Broca (Ang et al., 2003). — Some of the benefits of exercise on learning may be attributable to its effects on mechanisms of synaptic plasticity. LTP, which is a durable increase in the strength of a synapse after being repeatedly stimulated, appears to be the basis for memory formation, in that it can be induced by learning alone (Whitlock et al., 2006). In the dentate gyrus of the hippocampus, benefits of exercise have been observed on both neurogenesis (Pereira et al., 2007) and LTP (Farmer et al., 2004). Finally, exercise also alters the length and complexity of dendrites and of the density of the spines found on dendrites (Eadie et al., 2005). These exercise-induced dendritic changes can improve the efficiency of communication between neurons.”
The discussion in the publication goes on to point out that factors favoring brain plasticity include many of the “usual suspect” healthy lifestyle and dietary patterns and supplements that I have discussed in multiple past blog entries including confronting daunting mental challenges, avoidance of dietary fat, adherence to a Mediterranean-type diet , and taking omega-3 fatty acids and resveratrol.
Curcumin is also a powerful promoter of neurogenesis in the hippocampus
The August 2010 blog entry Neurogenesis, curcumin and longevity is specifically concerned with the impact of the dietary supplement curcumin on neurogenesis in the hippocampus and the impact of curcumin neural plasticity.
All behavioral experience as well as lifestyle patterns are reflected in epigenetic records which impact neuron and synapse formation in the hippocampus
I have written frequently about the all-pervasive effects of epigenetic records in the aging process. A specific discussion of such an effect is provided in the 2010 publication Synaptogenesis in adult-generated hippocampal granule cells is affected by behavioral experiences. “Adult-generated hippocampal immature neurons play a functional role after integration in functional circuits. Previously, we found that hippocampus-dependent learning in Morris water maze affects survival of immature neurons, even before they are synaptically contacted. Beside learning, this task heavily engages animals in physical activity in form of swimming; physical activity enhances hippocampal neurogenesis. In this article, the effects of training in Morris water maze apparatus on the synapse formation onto new neurons in hippocampus dentate gyrus and on neuronal maturation were investigated in adult rats. — The main result we found was the anticipated appearance of GABAergic synapses at 6 days in learner, cued and swimmer rats, supported also by immunohistochemical result. Swimmer rats showed the highest percentage of GFP-positive neurons with glutamatergic response at 10 and 12 days postmitosis. Moreover, primary dendrites were more numerous at 7 days in learner, cued and swimmer rats and swimmer rats showed the greatest dendritic tree complexity at 10 days. Finally, voltage-dependent Ca(2+) current was found in a larger number of newborn neurons at 7 days postinfusion in learner, cued and swimmer rats. In conclusion, experiences involving physical activity contextualized in an exploring behavior affect synaptogenesis in adult-generated cells and their early stages of maturation.”
The 2010 publication An epigenetic hypothesis of aging-related cognitive dysfunction suggests “a new hypothesis for the role of epigenetic mechanisms in aging-related disruptions of synaptic plasticity and memory. Epigenetics refers to a set of potentially self-perpetuating, covalent modifications of DNA and post-translational modifications of nuclear proteins that produce lasting alterations in chromatin structure. These mechanisms, in turn, result in alterations in specific patterns of gene expression. Aging-related memory decline is manifest prominently in declarative/episodic memory and working memory, memory modalities anatomically based largely in the hippocampus and prefrontal cortex, respectively. The neurobiological underpinnings of age-related memory deficits include aberrant changes in gene transcription that ultimately affect the ability of the aged brain to be “plastic”. The molecular mechanisms underlying these changes in gene transcription are not currently known, but recent work points toward a potential novel mechanism, dysregulation of epigenetic mechanisms. This has led us to hypothesize that dysregulation of epigenetic control mechanisms and aberrant epigenetic “marks” drive aging-related cognitive dysfunction.” The article focuses on “reviewing current knowledge concerning epigenetic molecular mechanisms, as well as recent results suggesting disruption of plasticity and memory formation during aging.”
Wrapping it up
· There are several important changes in human brains that typically start in middle age and that accelerate with advancing age: hippocampus size decreases, BDNF expression decreases, there is significant shrinkage of gray matter; there is a decrease in neurogenesis and often but not always decrease in cognitive capability and loss of memory.
· Shrinking of the hippocampus, the prefrontal cortex, entorhinal cortex, and caudate nucleus in late adulthood are thought to contribute to the patterns of cognitive and memory decline often observed in older adults.
· Age-related loss of neurogenesis is thought to be a main factor leading to age-related decline. Neurogenesis in the brain is a tightly controlled lifelong process. It primarily takes place in neurogenic niches in parts of the hippocampus. New neurons migrate to their destination locations.
· Disorders in BDNF gene expression are implicated in many aberrant mental conditions and Alzheimer’s disease. BDNF expression decreases with age and age-related loss in BDNF expression is thought to lead to hippocampal shrinking with age.
· Maintaining neuronal and cognitive plasticity is important for averting age-related memory decline and cognitive aging.
· Cognitive and memory decline with age is not inevitable and can be influenced by many factors. Neurogenesis, BDNF expression and synaptic plasticity are highly dynamic processes in healthy individuals. They can be upregulated with physical and mental exercise, good lifestyle patterns, via good diet and via taking certain supplements including resveratrol, curcumin and omega3 fatty acids.
· Epigenetic regulation of brain aging is a new topic that I expect will attract significant attention as time progresses, revealing the behavior-driven gene-activation mechanisms that affect brain aging and the mechanisms that inhibit such aging.
· Besides the materials discussed here, a search of the index of this blog will reveal many additional articles on the key topics discussed here as well as many related topics such as Alzheimer’s disease.