Age-related cognitive decline: focus on interventions

In previous blog entries and in my longevity treatise, I have discussed factors involved in age-related decline in memory and cognitive functioning.  This blog entry is concerned with research findings that suggest practical approaches to slowing or possibly reversing such age-related decline. 

I am motivated in part by several personal requests I have had from friends and associates along the lines of “Can you tell me what to do to maintain my mental acuity and memory as I grow older?”  And, soon to turn 82, I am very interested in the topic for myself.  To the extent that the interventions I suggest relate to basic neural processes, they may also possibly help with other age-related declines such as in hearing, vision, smell, spatial perception, balance, athletic capabilities and sleep disturbance.  Also they are useful for avoiding mood disorders, maintaining a positive mental attitude and not turning grumpy.  This is a long blog post and I summarize my main conclusion at the end.


One factor that appears to be implicated in age-related cognitive decline is age-related decline in the rate of differentiation of neural stem cells which replenish senescent or expired neural cells.  An introduction to this concept is included in my treatise in the section on the Neurological degeneration theory of aging.   I strongly suggest reviewing the April; 2011 blog entry Age-related memory and brain functioning – focus on the hippocampusThat blog entry discusses multiple factors implicated in age-related physical brain changes and normal decline of memory and brain functioning.  And, it deals secondarily with possible interventions.  That blog entry also discuss how age-related decline in expression of BDNF (brain-derived neurotrophic factor) is also involved in cognitive and memory decline.  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.  I will refer to several other blog entries in context. 

Increasing neurogenesis and BDNF expression are two key factor that can be worked with to offset declines in mental acuity and memory retention.  A third such factor is increasing mitochondrial activity in nerve cells.  This includes both improving mitochondrial metabolism and promoting mitochondrial biogenesis.  See the blog entries PQQ – activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, AMPK and longevity, and PGC-1alpha and exercise.  Other factors I mention also can impact negatively on the health of nerve cells such as oxidative stress(ref) ,microglial activation(ref) and accumulation of lipofuscin(ref).

My assumption here is that increasing neurogenesis and BDNF expression can offset declines in mental acuity and memory retention.  Recent research suggests strongly that this is the case.  The July 2011 publication Requirement of adult-born neurons for hippocampus-dependent learning reports  A fundamental question in the field of adultneurogenesis relies in addressing whether neurons generated in the adult dentate gyrus are needed for hippocampal function. Increasing evidence is accumulating in support of the notion that hippocampus-dependent behaviors activate new neurons and that those neurons are highly relevant for information processing. More specifically, immature new neurons under development that have unique functional characteristics begin to emerge as a highly relevant population in the dentate gyrus network. This review focuses on how hippocampus-dependent behaviors activate adult-born neurons and how modulation and ablation of adult hippocampal neurogenesis alter spatial and associative memory. While several contradictory findings emerge when analyzing the literature, evidence in favor of a relevant role of adult-born neurons in hippocampal function is compelling.”

The 2011 publication Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation relates  Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adultneurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behavior. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.”

While both increasing neurogenesis and increasing BDNF expression are both known to increase mental acuity, learning and memory, it is not exactly clear what the causal chain is.  A July 2011 publication again highlights the critical role of BDNF in mental acuity:   Effects of environmental enrichment and voluntary exercise on neurogenesis, learning and memory, and pattern separation: BDNF as a critical variable?  Adult-generated neurons in the dentate gyrus of the hippocampus have been the focus of many studies concerned with learning and memory (L&M). It has been shown that procedures like environmental enrichment (EE) or voluntary physical exercise (Vex) can increase neurogenesis (NG) and also enhance L&M. It is tempting to conclude that improvements in L&M are due to the increased NG; that is, a causal relationship exists between enhancement of NG and enhancement of L&M. However, it remains unclear whether the L&M enhancement observed after these treatments is causally dependent on the increase in newborn neurons in the dentate gyrus. It remains a possibility that some unspecified change – a “third variable” – brought about by EE and/or Vex could be a causal determinant of both NG and L&M. We suggest that this third variable could be neurotrophic and/or plasticity-related factors such as BDNF. Indeed, both EE and Vex can induce expression of such proteins, and BDNF in particular has long been linked with L&M. In addition, we argue that a very likely source of variation in previous experiments was the load on “pattern separation”, a process that keeps similar memories distinct, and in which NG has been shown to be critically involved. To attempt to bring these ideas together, we present preliminary evidence that BDNF is also required for pattern separation, which strengthens the case for BDNF as a candidate third variable.”

The factors that cause decline in neurogenesis and BDNF expression and therefore decline in cognition and memory with aging are becoming known.

One such factor is Wnt3 protein expression.  The July 2011 e-publication Reduction in paracrine Wnt3 factors during aging causes impaired adult neurogenesis tells the story.  The mammalian brain contains neural stem cells (NSCs) that enable continued neurogenesis throughout adulthood. However, NSC function and/or numbers decline with increasing age. Adult hippocampal neurogenesis is unique in that astrocytes secreting Wnt3 promote NSC differentiation in a paracrine manner.” (Paracrine signalling is a form of cell signalling in which the target cell is near (“para” = near) the signal-releasing cell.)  “Here, we show that both the levels of Wnt3 protein and the number of Wnt3-secreting astrocytes influence the impairment of adultneurogenesis during aging. The age-associated reduction in Wnt3 levels affects the regulation of target genes, such as NeuroD1 and retrotransposon L1, as well as the expression of Dcx, which is located adjacent to the L1 loci. Interestingly, the decline in the extrinsic Wnt3 levels and in the intracellular expression of the target genes with aging was reversible. Exercise was found to significantly increase de novo expression of Wnt3 and thereby rescue impaired neurogenesis in aged animals. Furthermore, the chromatin state of NeuroD1, L1, and the L1 loci near Dcx changed relative to Wnt3 levels in an age- or stimulus-associated manner. These results suggest that the regulation of paracrine factors plays a critical role in hippocampal aging and neurogenesis.”  You can also see the 2010 publication Wnt-3a and Wnt-3 differently stimulate proliferation and neurogenesis of spinal neural precursors and promote neurite outgrowth by canonical signaling and the 2008 review Wnt signaling in neuroprotection and stem cell differentiation.

The recent blog entry Longevity of stem cells and the roles of stem cells in agingdiscusses properties of neural stem and progenitor cells among others and the epigenetic mechanisms involved in neural stem cell self-renewal and proliferation.

I organize the rest of this blog entry according to practical interventions to avert or reverse age-related decline in memory and cognitive functioning.  In the process I cite a number of 2011 and earlier publications not cited in earlier blog entries.

Memory and mental acuity and sleep patterns

Establishing a regular pattern of sound sleep can help a lot.  A series of research publications suggest that a regular pattern of sound sleep fosters neurogenesis and expression of BDNF while disturbed or inadequate sleep leads to a precipitous decline in neurogenesis.

The 2008 review publication New neurons in the adult brain: the role of sleep and consequences of sleep loss relates “In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. — Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. — Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.”

The unfolded protein response (UPR) appears to be a response to sleep-deprivation stress.  The 2009 publication Cellular stress/the unfolded protein response: relevance to sleep and sleep disorders reports “Recent transcript profiling and microarray studies are beginning to unveil some of the mysteries of sleep. One of the most important clues has been the identification of the endoplasmic reticulum (ER) resident chaperone, immunoglobulin binding protein (BiP), that increases with sleep deprivation in all species studied. BiP, an ER resident chaperone, is the key cellular marker and master regulator of a signaling pathway called the ER stress response or unfolded protein response. The ER stress response occurs in 3 phases. It is healthy, protective and adaptive when the ER stress is moderate. Failure of the adaptive response leads to the activation of an inflammatory response. When the ER stress burden is great and prolonged, executioner pathways are activated. Collectively this work provides new evidence that modest sleep deprivation induces cellular stress that activates an adaptive response. Aging tilts the response to sleep deprivation from one that is adaptive and protective to one that is maladaptive. Understanding the pathways activated by sleep loss and the mechanisms by which they occur will allow the development of therapies to protect the brain during prolonged wakefulness and specifically in sleep disorders including those associated with aging.”  The unfolded protein response (UPR) is discussed in the blog entry HSP70 to the rescue.

Aging gets in the way of the UPR response to sleep deprivation leading to neurons being killed as pointed out in the 2008 publication Aging impairs the unfolded protein response to sleep deprivation and leads to pro-apoptotic signaling.  Protein misfolding, accumulation, and aggregation characterize many aging-related diseases. Protein aggregates do not accumulate in unstressed cells primarily because of the existence of competent cellular “quality control” machinery. The endoplasmic reticulum (ER) is a major part of this quality control system. Accumulation of misfolded proteins in the ER causes ER stress and activates a signaling pathway called the unfolded protein response (UPR). The UPR limits protein load by upregulating ER chaperones such as Ig binding protein (BiP)/glucose-regulated protein 78 (GRP78) and by attenuating protein translation through eukaryotic initiation factor 2 alpha (eIF2alpha) phosphorylation. Acute sleep deprivation (6 h) in young mice leads to induction of the UPR with upregulation of BiP/GRP78 and attenuation of protein translation. We demonstrate here that aging impairs this adaptive response to sleep deprivation. Aged mice do not display an increase in BiP expression with acute sleep deprivation. In addition, there is decreased basal expression of BiP/GRP78 in aged mice. There is a decline in eIF2alpha phosphorylation in aged mouse cerebral cortex that is associated with higher levels of GADD34 (growth arrest and DNA damage 34) and proapoptotic proteins such as CCAAT/enhancer-binding protein-homologous protein and activated caspase-12, suggesting that young animals possess an efficient ER adaptive response that declines with aging.”

A number of additional recent publications deal with the relationship of sleep to neurogenesis.  I mention only the July 2011 publication Inhibition of hippocampal neurogenesis by sleep deprivation is independent of circadian disruption and melatonin suppressionProcedures that restrict or fragment sleep can inhibit neurogenesis in the hippocampus of adult rodents, although the underlying mechanism is unknown. — Consistent with our previous results, the RSD (rapid-eye-movement sleep deprivation) procedure suppressed cell proliferation by 50%. By contrast, although LL attenuated or eliminated daily rhythms of activity and sleep-wake without affecting daily amounts of REM sleep, cell proliferation was not affected. Melatonin, a nocturnally secreted neurohormone that is inhibited by light, has been shown to promote survival of new neurons. We found that 3-weeks of LL (constant bright light) eliminated daily rhythms and decreased plasma melatonin by 88% but did not significantly affect either total cell survival or survival of new neurons (doublecortin+). — These results indicate that the antineurogenic effect of RSD is not secondary to disruption of circadian rhythms, and provide no evidence that hippocampal cell proliferation and survival are regulated by the circadian system or by nocturnal secretion of pineal melatonin.”

Memory and mental acuity and regular physical exercise

Physical exercise is a cornerstone in any mental-acuity enhancing program.  It increases neurogenesis and increases expression of BDNF.  I personally supplement my normal physical activity with 44 minutes of fairly vigorous exercise every day – swimming, treadmilling, fast hiking or rigorous yard work.  

Knowledge that exercise fosters neurogenesis goes back a number of years.  The 2008 publication Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice summed it up “Taken together, mandatory running exercise alters the brain chemistries of middle-aged animals toward an environment that is favorable to NSC proliferation, survival, and maturation.”

The 2009 publication Exercise increases neural stem cell number in a growth hormone-dependent manner, augmenting the regenerative response in aged mice concludes “These findings now provide a novel basis for understanding the ability of exercise to delay the onset and rate of decline in neurodegenerative conditions not typically associated with the hippocampus and suggest that the GH-dependent activation of endogenous NSCs may be effective in reversing or preventing age-related neurodegeneration in humans.”

In the blog entry Age-related memory and brain functioning – focus on the hippocampus, I related: “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 reportsThe 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.”

IGF1 (insulin growth factor 1) is a pathway closely related to longevity that has been discussed several times before in this blog, such as in Victor’s post Longevity and the GH–IGF Axis.  Generally, suppression of this pathway in smaller animals leads to longer lives.  IGF-1 expression is also modulated by exercise so as to affect neurogenesis.  The 2010 publication Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour reports “While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety–as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of exercise, as well as to extend the role of serum IGF1 in the brain in basal conditions. Moreover, these data reveal the complexity of the interaction between neurogenesis, behaviour, and IGF1 under different levels of physical activity.”

Memory and mental acuity and melatonin

Supplementation with melatonin can be used to help maintain a regular sleep pattern, maintain regular neurogenesis and protect against stress-induced impairment of neurogenesis. 

See the 2011 publication Chronic treatment with melatonin stimulates dendrite maturation and complexity in adult hippocampal neurogenesis of mice. “In the course of adult hippocampal neurogenesis, the postmitotic maturation and survival phase is associated with dendrite maturation. Melatonin modulates the survival of new neurons with relative specificity. During this phase, the new neurons express microtubule-associated protein doublecortin (DCX). Here, we show that the entire population of cells expressing DCX is increased after 14 days of treatment with melatonin. As melatonin also affects microtubule polymerization which is important for neuritogenesis and dendritogenesis, we studied the consequences of chronic melatonin administration on dendrite maturation of DCX-positive cells. Treatment with melatonin increased the number of DCX-positive immature neurons with more complex dendrites. Sholl analysis revealed that melatonin treatment lead to greater complexity of the dendritic tree. In addition, melatonin increased the total volume of the granular cell layer. Besides its survival-promoting effect, melatonin thus also increases dendritic maturation in adult neurogenesis. This might open the opportunity of using melatonin as an adjuvant in attempts to extrinsically stimulate adult hippocampal neurogenesis in neuropsychiatric disease, dementia or cognitive ageing.”

Also see Melatonin maintains adult hippocampal neurogenesis and cognitive functions after irradiation(2010), Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice (2008), Melatonin promotes neurogenesis in dentate gyrus in the pinealectomized rat (2009)

Memory and mental acuity and plant-derived polyphenols

A number of foods and plant-derived substances can slow or prevent cognitive decline.  Again, this has been a recurring theme in this blog.  See, for example, the blog entries Health and longevity benefits of plant polyphenols – focus grape seed extract, Focus on ginger, Back to blueberries, Blueberries and health – the research case,Warding off Alzheimer’s Disease and things in my diet (including lots of coffee, walnuts and chocolate).

Memory and mental acuity and avoiding toxins and infectious agents, nitrates and nitrites.

Toxins as well as infectious agents can impair neurogenesis(ref)(ref).  See the blog entries Nitrates and nitrites – Part 1: bad for you and Warding off Alzheimer’s Disease and things in my diet

Memory and mental acuity can be negatively impacted by severe infection, but the impact may be offset by probiotic supplementation

The August 2011 e-publication Bacterial infection causes stress-induced memory dysfunction in mice reports “BACKGROUND: The brain-gut axis is a key regulator of normal intestinal physiology; for example, psychological stress is linked to altered gut barrier function, development of food allergies and changes in behaviour. Whether intestinal events, such as enteric bacterial infections and bacterial colonisation, exert a reciprocal effect on stress-associated behaviour is not well established.  OBJECTIVE: To determine the effects of either acute enteric infection or absence of gut microbiota on behaviour, including anxiety and non-spatial memory formation.  METHODS: Behaviour was assessed following infection with the non-invasive enteric pathogen, Citrobacter rodentium in both C57BL/6 mice and germ-free Swiss-Webster mice, in the presence or absence of acute water avoidance stress. Whether daily treatment with probiotics normalised behaviour was assessed, and potential mechanisms of action evaluated.  RESULTS: No behavioural abnormalities were observed, either at the height of infection (10 days) or following bacterial clearance (30 days), in C rodentium-infected C57BL/6 mice. When infected mice were exposed to acute stress, however, memory dysfunction was apparent after infection (10 days and 30 days). Memory dysfunction was prevented by daily treatment of infected mice with probiotics. Memory was impaired in germ-free mice, with or without exposure to stress, in contrast to conventionally reared, control Swiss-Webster mice with an intact intestinal microbiota.  CONCLUSIONS: The intestinal microbiota influences the ability to form memory. Memory dysfunction occurs in infected mice exposed to acute stress, while in the germ-free setting memory is altered at baseline.”

Memory and mental acuity and pregnenoone supplementation

Supplementation with the hormone pregnenolone is likely to facilitate neurogenesis.

A 2009 review publication points to a powerful hormone promoter of neurogenesis, allopregnanolone: Therapeutic potential of neurogenesis for prevention and recovery from Alzheimer’s disease: allopregnanolone as a proof of concept neurogenic agent.These endeavors have led to the discovery that the neurosteroid alloprognanolone (APalpha) is a potent and highly efficacious proliferative agent in vitro and in vivo of both rodent and human neural stem cells. Results of our in vitro studies coupled with our more recent analyses in the triple transgenic mouse model of AD suggest that APalpha is a promising strategy for promoting neurogenesis in the aged brain and potentially for restoration of neuronal populations in brains recovering from neurodegenerative disease or injury. A brief overview of issues impacting the therapeutic potential of neurogenesis and the factors used to promote neurogenesis in the aging and degenerating brain is presented. Also included is a review of our current research into the neurogenic potential of the small molecule, blood brain barrier penetrating, neurosteroid allopregnanolone (APalpha).”

A 2010 publication Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer’s disease demonstrated that allopregnanolone actually worked to reverse Alzheimer’ disease cognitive deterioration in a mouse model.  “Our previous analyses showed that allopregnanolone (APalpha) significantly increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory deficits in 3-month-old male triple transgenic mouse model of Alzheimer’s (3xTgAD) and the correlation between APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. — 3xTgAD mice exhibited deficits in learning and memory. APalpha reversed the cognitive deficits to restore learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APalpha-induced survival of neural progenitors was significantly correlated with APalpha-induced memory performance. These findings suggest that early neurogenic deficits, which were evident before immunodetectable Abeta, may contribute to the cognitive phenotype of AD, and that APalpha could serve as a regenerative therapeutic to prevent or delay neurogenic and cognitive deficits associated with mild cognitive impairment and Alzheimer’s disease.”

Allopregnanolone or pregnanone are not the same substance as the hormone supplement pregnenolone, but the substances are very similar in chemical structure and possibly activity.  In fact, pregnenolone itself has been shown to promote neurogenesis. The 2005 publication Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus reports “We demonstrate that in vivo infusion of Preg-S stimulates neurogenesis and the expression of the polysialylated forms of NCAM, PSA-NCAM, in the dentate gyrus of 3- and 20-month-old rats. These influences on hippocampal plasticity are mediated by the modulation of the gamma-aminobutyric acid receptor complex A (GABAA) receptors present on hippocampal neuroblasts. In vitro, Preg-S stimulates the division of adult-derived spheres suggesting a direct influence on progenitors. — These data provide evidence that neurosteroids represent one of the local secreted signals controlling hippocampal neurogenesis. Thus, therapies which stimulate neurosteroidogenesis could preserve hippocampal plasticity and prevent the appearance of age-related cognitive disturbances.”

Memory and mental acuity and environmental enrichment

Experiencing a rich complex environment is another way to promote neurogenesis(ref)(ref)(ref).  This applies to both physical and social environment and intellectual environment affecting learning..

Mental activity and mental exercise can definitely foster both neurogenesis and the existence of a sharp mental condition.

I have written about this before.  See the blog entries Brain fitness, Google and comprehending longevity and Mental exercise and dementia in the news again.

Memory and mental acuity and social interaction

Social environments can strongly affect neurogenesis.  Again, the richer and more supportiuve the environment, the stronger the affect in promoting neurogenesis.  See Modification of hippocampal neurogenesis and neuroplasticity by social environments.  “These findings demonstrated that social environments can modify neurogenesis and synaptic plasticity in adult hippocampal regions, which is associated with alterations in spatial learning and memory.”

Memory and mental acuity and resveratrol

Of particular relevance, the plant-derived polyphenol resveratrol can promote neurogenesis.  See Neurogenesis directed by Sirt1,  Resveratrol improves hippocampal atrophy in chronic fatigue mice,   and Resveratrolfor Enriching Neurogenesis & Memory in the agedAlso, you can see the discussion in my blog entryAge-related memory and brain functioning – focus on the hippocampus.  

Memory and mental acuity and omega fish oils

As part of fighting off cognitive decline, It is a good idea to include omega fish oils in your supplement list.

The 2011 publication Omega-3 polyunsaturated fatty acid supplements and cognitive decline: Singapore Longitudinal Aging Studiesreports “OBJECTIVE: To determine the association between long chain omega-3 polyunsaturated fatty acid (n-3 PUFA) supplements intake and cognitive decline in an older Chinese population. DESIGN: Prospective cohort study.SETTING: The Singapore Longitudinal Aging Studies (SLAS), a community-based study in urban region of Singapore. PARTICIPANTS: 1,475 Chinese adults aged ≥ 55 years. MEASUREMENT: Omega-3 PUFA supplements intake and Mini-Mental State Examination (MMSE) were assessed at baseline. MMSE was re-assessed at a median of 1.5 years after baseline and cognitive decline was defined as at least 2-points drop in MMSE score from baseline to follow-up. Odds ratios (ORs) of association between n-3 PUFA supplements intake and cognitive decline were calculated in logistic regression models controlling for baseline confounding variables. RESULTS: Daily n-3 PUFA supplements intake was significantly (p=0.024) associated with lower risk of cognitive decline (OR=0.37, 95% C.I. 0.16-0.87) after controlling for age, gender, education, number of medical comorbidity, the presence of vascular risk factors/diseases, smoking, alcohol drinking, depression, APOE e4 allele carrier status, nutritional status, level of leisure activities, baseline MMSE and length of follow-up. The association remained significant (p=0.015) after excluding participants with baseline cognitive impairment (MMSE < 24), diabetes, stroke, and cardiac diseases (OR=0.23, 95% C.I. 0.07-0.75). No statistically significant association (OR=1.02, 95% C.I. 0.81-1.27) of fish consumption with cognitive decline was found. CONCLUSION: Daily n-3 PUFA supplements consumption was independently associated with less cognitive decline in elderly Chinese.”

See also the 2011 publication Fish oil promotes survival and protects against cognitive decline in severely undernourished mice by normalizing satiety signals.

Memory and mental acuity and other key supplements

 Lipofuscin, a metabolic waste, can accumulate in nerve cells impairing their functionality(ref)(ref)(ref).  As stated in the blog entry Research Roundup on the Lipofuscin Theory of Aging:  “Large accumulations of lipofuscin and lipofuscin-like materials in cells can lead to cell death. — The results of this study are consistent with the conclusion that accumulation of lipofuscin-like materials results in inhibition of the proteasome, which initiates an apoptotic cascade as a result of dysregulation of several proapoptotic proteins(ref).”Several of the antioxidants in my combined anti-aging supplement regimen function so as to reduce levels of lipofuscin accumulation in brain and other cells, including l-carnosine, alpha-lipoic acid, CoQ10 and curcumin. Piracetam, another firewall component, appears to significantly decrease the formation of lipofuscin in neurons. I take two supplements which have a capability to pump lipofuscin out of cells. One is meclofenoxate (centrophenoxine) a ‘smart drug” used in Europe to treat symptoms of senile dementia and Alzheimer’s disease. The other is acetyl-l-carnitine, a pluripotent antioxidant.  These substances and alpha-lipoic acid operate on the mitochondria and have important impacts on nerve and other cell metabolism also useful for mitochondrial health.  See this list of publications, (ref),(ref),(ref),(ref),(ref),(ref), and the blog entry The curious case of l-carnosine.

Memory and mental acuity and curcumin

Supplementation with curcumin can be definitely helpful.  I have devoted a blog entry specifically to this topic Neurogenesis, curcumin and longevity.

Memory and mental acuity and folic acid

Folic acid supplementation may help.  The 2011 publication Beneficial effects of folic acid on enhancement of memory and antioxidant status in aged rat brainreports “Clinical, biochemical, and pathological aspects have shown a correlation between mental symptoms, especially depression and cognitivedecline, with high incidence of folate deficiency (Bottiglieri et al., J Neurol Neurosurg Psychiatry 69:562, 2000). In the present study, consequences of folic acid supplementation on brain dysfunction as a result of aging were studied in cerebral cortex, mid brain, and cerebellar regions of rat brain. This study was carried out on 6-, 11-, and 16-month-old rats, which received folic acid at a dose of 5 mg/kg body weight/day for a period of 8 weeks. Respective control groups of the same age groups were also taken. At the end of the treatment duration, behavioral studies were performed and later the animals were killed for various biochemical and histological investigations. Results indicated significant improvement in memory as assessed by active avoidance, passive avoidance, and plus maze tests in the folic acid supplemented aged animals. Significant improvement was also seen in the cellular protective mechanisms where by the activity of superoxide dismutase and catalase enzymes increased in folic acid supplemented group and so was the glutathione content. Increased lipid peroxidation content, a marker of aging, was also found to be decreased during folic acid supplementation in all the three regions of brain in our study. Thus, it can be concluded that folic acid helps in improving the memory status by reducing oxidative stress and maintaining the integrity of neurons during aging.”

I caution that excess folic acid intake has been implicated in possibly inducing cancer risk associated with GPC island methylation. See the blog post The many faces of folic acid.

Memory and mental acuity and PQQ

The substance PQQ works on the level of mitochondria, including in nerve cells, and affects their metabolism.  it stimulates the generation of PGC1-alpha, results in expression of SIRT3, and induces mitochondrial biogenesis.  Further PQQ is known to be neuroprotective under certain stress conditions.  See the blog entries PQQ – activator of PGC-1alpha, SIRT3 and mitochondrial biogenesis, AMPK and longevity and PGC-1alpha and exercise.  PQQ has been called “exercise in a pill” since PQQ stimulates PGC1-alpha and PGC-1alpha is thought to be the health mediator of exercise.

Wrapping it up

The many practical interventions that enhance cognition and memory described above share some interesting properties. 

  • First, there is not one simple approach to promoting memory and mental acuity, neurogenesis and healthy nerve cell metabolism, nor is there even a small handful.  To get the best results it is likely that a large number of approaches should be pursued synergistically.
  •  Second, though based on up-to-date research, without exception the interventions discussed above have been and are elements of the anti-aging lifestyle and supplement firewall regimens in my treatise. 
  • Third, though looked at here from the viewpoint of one particular theory of aging, Neurological Degeneration, the interventions also combat aging from the viewpoints of essentially all of the other theories of aging.

The implication is that neurological mental health and delaying of decline in memory and cognitive capability is intrinsically bound up with health in general and delaying other negative symptoms of advanced aging.  The research findings described above in my mind provide additional strong support for the combined anti-aging lifestyle and supplement regimens.

About Vince Giuliano

Being a follower, connoisseur, and interpreter of longevity research is my latest career. I have been at this part-time for well over a decade, and in 2007 this became my mainline activity. In earlier reincarnations of my career. I was founding dean of a graduate school and a university professor at the State University of New York, a senior consultant working in a variety of fields at Arthur D. Little, Inc., Chief Scientist and C00 of Mirror Systems, a software company, and an international Internet consultant. I got off the ground with one of the earliest PhD's from Harvard in a field later to become known as computer science. Because there was no academic field of computer science at the time, to get through I had to qualify myself in hard sciences, so my studies focused heavily on quantum physics. In various ways I contributed to the Computer Revolution starting in the 1950s and the Internet Revolution starting in the late 1980s. I am now engaged in doing the same for The Longevity Revolution. I have published something like 200 books and papers as well as over 430 substantive.entries in this blog, and have enjoyed various periods of notoriety. If you do a Google search on Vincent E. Giuliano, most if not all of the entries on the first few pages that come up will be ones relating to me. I have a general writings site at and an extensive site of my art at Please note that I have recently changed my mailbox to
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12 Responses to Age-related cognitive decline: focus on interventions

  1. hanglin says:

    Dear Vincent : wih my respect, I like your post very much, since I am intereted in the ant-ageing area recently. do you have any hint of Iron and Ageing? thank you very much!

  2. JEG3 says:

    Hi Vince,

    Nice write up, cognitive ability and mobility are definite pluses.
    Just saw this article which is hopeful:

    Another semi-related topic, have you read Michael Rose’s latest book:
    Also talks about it in this video:

    Your anti-aging plan may keep you on a lower late-life mortality plateau.
    I’m still mentally digesting the book, need to read it a few more times.

  3. JEG3:

    Thanks for the suggested reads and video. The video is fascinating though I am not positive I agree with the possibility of the antiaging strategy suggested by Rose. The data on human longevity does not support the Rose notion that aging stops at some point and after that the probability of death essentially remains constant. If that were the case we would have a few people – albeit very few – who lived to 150, 200, 300 etc. That is the nature of a Poissonian distribution implied by a constant attrition rate. As we know, instead everybody dies by 122. No exception so far. Yet there may be something to his notion that the rate of aging levels at some point and, yes, I am striving to stay of a lower mortality plateau.


  4. Hanglin

    Sorry, to this point I have not really looked very hard of the role of iron. I might do that some time.


  5. eric25001 says:

    Here are some comments and links about some older blood pressure medications that seem to have a positive effect for cognative decline and heart disease.

    This relates to the previous post on Guanfacine (TENEX) also a blood pressure medicine that helped with cognative decline. Upside of lower blood pressure and youthful like rejuventation of mitochondria seem like good reasons to ask about low 2 mg dose of Guanfacine or losartan the blood pressure drug mentioned in this article.

    Eric Live Long and Prosper!

    Contact: John Lazarou
    Johns Hopkins Medical Institutions

    Switch in cell’s ‘power plant’ declines with age, rejuvenated by drug
    Researchers at the Johns Hopkins University School of Medicine have found a protein normally involved in blood pressure regulation in a surprising place: tucked within the little “power plants” of cells, the mitochondria. The quantity of this protein appears to decrease with age, but treating older mice with the blood pressure medication losartan can increase protein numbers to youthful levels, decreasing both blood pressure and cellular energy usage. The researchers say these findings, published online during the week of August 15, 2011, in the Proceedings of the National Academy of Sciences, may lead to new treatments for mitochondrial–specific, age-related diseases, such as diabetes, hearing loss, frailty and Parkinson’s disease.

    “We’ve identified a functional and independently operated system that appears to influence energy regulation within the mitochondria,” explains Jeremy Walston, M.D., professor of geriatric medicine at Hopkins. “This mitochondrial angiotensin system is activated by commonly utilized blood pressure medications, and influences both nitric oxide and energy production when signaled.”

    Previous research showed that manipulating angiotensin in the body’s cells had unexpectedly affected mitochondrial energy production, so Walston and Peter Abadir , M.D., an assistant professor of geriatric medicine, decided to examine the role of angiotensin within the mitochondria. Using high-powered microscopy, they and their collaborators found evidence within the mitochondria of angiotensin as well as one of the protein receptors that bind to and detect it. They also pinpointed the angiotensin receptor’s exact locations within the mitochondria of mouse kidney, liver, neuron and heart cells as well as in human white blood cells.

    The team then treated mitochondria with a chemical known to activate the angiotensin receptors and measured the cell’s response. This resulted in a decrease in oxygen consumption by half and a small increase in nitric oxide production—indicating less energy made by the mitochondria and lowered blood pressure, respectively. Explains Walston, “Activating angiotensin receptors within the mitochondria with these agents led to lowered blood pressure and decreased cellular energy use.”

    But they found even more than just an energy-regulating mechanism; after testing the angiotensin system in mitochondria of both young and old mice, they noticed a decrease by almost a third of the amount of the angiotensin receptor type 2 in the mitochondria in older mice, meaning that cells in older mice were unable to control energy use as well. The researchers then tried treating these older mice with the blood pressure lowering drug losartan daily for 20 weeks and found that the number of these receptors increased. “Treatment of the old mice with losartan resulted in a marked increase in the number of receptors that are known to positively influence blood pressure and decrease inflammation,” says Walston.

    Declining mitochondria are known to influence chronic diseases in older adults, explains Walston, whose next step is to translate studies from cell culture and animal based studies to human studies in hopes of developing new therapies. “Our findings will help us determine if the drugs that interact with this receptor will also lead to improvement of mitochondrial function and energy production. This, in turn, could facilitate the treatment of a number of chronic diseases of older adults.”


    This study was funded by the Johns Hopkins Older Americans Independence Center, the National Institute on Aging and the American Geriatrics Society.

    Additional authors on this study from the Division of Geriatric Medicine and Gerontology at Johns Hopkins were Peter Abadir, Alka Jain, and Neal Fedarko.

  6. eric25001 says:

    Here is where this comment on this article belongs. Eric

    The hunt for blood substances that slow brain aging
    September 2, 2011 by Editor
    Stanford University School of Medicine scientists have found substances in the blood of old mice that make young brains act older.

    The researchers connected the circulatory systems of pairs of old and young mice via a surgical procedure, which produced brain changes in areas critical to memory and learning (like the hippocampus) in both type of mice: the older mouse of the pair produced more new nerve cells, while the young one produced fewer.

    So what in the blood was producing the effect? When they analyzed different immune-signaling proteins, they found high concentrations of six of them in the blood of both unpaired old mice and young mice that had been paired with older ones.

    At the top of the list was eotaxin, a small protein that impaired performance on spatial-memory tests, and in humans is associated with allergic responses and asthma. The negative effects of eotaxin could be countered by injections of another substance that blocks its action.

    The researchers speculated that it might be possible to shield the brain from aging by eliminating or mitigating the effects of these proteins, or perhaps by identifying other blood-borne substances that exert rejuvenating effects on the brain, but whose levels decline with age.

    Related news today: Faster diagnostics with cheap, ultra-portable blood testing

    Ref.: Saul A. Villeda, et al., The ageing systemic milieu negatively regulates neurogenesis and cognitive function, Nature, 2011; [DOI:10.1038/nature1035]

  7. Eric25001

    Thanks for these fascinating contributions. They suggest a couple of serious possible approaches to slowing or stopping age-related cognitive decline that are worth further looking into. I will track down the articles.


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