How to reduce brain decline with age (or maximize mindspan)

=> bigger dendritic spines also decrease less w/age than smaller dendritic spines


Exercising + playing RTS games when older (esp Sins of a Solar Empire/Rise of Nations can help). Strategy-Based Video Games May Improve Older Adults' Brain Function | American Association for the Advancement of Science


it’s worth looking up Wallerian degeneration - Wikipedia / - you want to keep NMNAT2 high. Neurons tend to shrink/shrivel rather than die. They are unique from other tissue in that they don’t divide (though they do lose A LITTLE bit of telomere) and how their synaptic/axonal properties ARE affected by age in a way very different from other tissue (in particular, larger spines decline less w/age), and processes that maintain spine size/density tend not to be the same processes that affect aging process in other tissues

also note hypothalamic inflammation is one thing that often makes people unable to control their hunger over time, DON’T EAT TOO MUCH, b/c ROS from feeling full is PRECISELY what controls hypothalamic inflammation.

also too much calcium is bad. Mg/Ca ratio is good to increase. Diffuse axonal injury - Wikipedia

POSSIBLY interesting (but not the most important thing):
Repair of Mitochondrial Recycling Defect Linked to Parkinson’s Disease - Neuroscience News

ALCOHOL is INTERESTING. higher levels are undoubtedly bad, but lower levels can promote glymphatic clearance - Alcohol promotes waste clearance in the CNS via brain vascular reactivity - PubMed (needs more info)

Kaempferol is interesting - high concentration in capers possibly, tho effect size is not large

this is so good -

Supplementation with ProdromeNeuro was observed to elevate blood DHA-plasmalogen levels. The increase in blood DHA-plasmalogens correlated with a decrease in malondialdehyde levels (r=-0.5, p=7.2e-07) and an increase in catalase activity (r=0.28, p=0.008). Superoxide dismutase activity was increased in persons with low baseline activity (p=0.017).

To access the FREE seminars with full presentations and videos please visit Dr. Goodenowe’s resource site here. This is the article for seminar C106, Supplements (Series C).

ProdromeNeuro is a plasmalogen supplement designed to specifically elevate DHA plasmalogen levels. An escalating dose study was performed in 22 persons (11M/11F) diagnosed with various degrees of cognitive impairment to determine the optimal dose for elevating blood plasmalogen levels.

In addition to clinical evaluations of cognition and mobility, blood samples were collected at baseline and after each month of supplement dosing for biomarker analyses.

The escalating dosing of ProdromeNeuro was performed as follows:

Month 1 – 1ml/day (900mg/day – one bottle of ProdromeNeuro)

Month 2 – 2ml/day (1800mg/day – two bottles of ProdromeNeuro)

Month 3 – 2ml/day (1800mg/day – two bottles of ProdromeNeuro)

Month 4 – 4ml/day (3600mg/day – four bottles of ProdromeNeuro)

Month 5 – 0ml/day (0mg/day – zero bottles of ProdromeNeuro)

Blood DHA-Plasmalogen levels were observed to be increased in all participants in a dose-dependent manner. After month 1 there was a 30% increase, after months 2 and 3 there was a 60% increase and after month 4 there was a 90% increase in the target DHA-plasmalogen levels. Persons with low baseline DHA-plasmalogen levels (quartiles 1 and 2) experienced a greater increase in blood DHA-plasmalogen levels (50%, 90%, and 120%, respectively). When blood DHA-plasmalogen levels were expressed relative to an endogenous non-DHA phosphatidylethanolamine, the relative increase in the target DHA plasmalogen levels was more pronounced.

The oxidative stress cascade begins with the formation of the superoxide radical resulting from a cellular insufficiency in recycling NADH back to NAD by the mitochondrial electron transport chain. A build-up of NADH beyond the intracellular capacity to recycle NADH by alternative, non-oxidative, anaerobic mechanisms leads to the export of free electrons to the extracellular environment by NAD(P)H oxidase (NOX). These electrons combine with molecular oxygen to form the superoxide radical. Superoxide is neutralized to molecular oxygen and hydrogen peroxide by superoxide dismutase both inside and outside of the cell. Hydrogen peroxide, in turn, is neutralized into molecular oxygen and water by multiple mechanisms such as catalase, glutathione peroxidase or by chemical neutralization by plasmalogens. The failure of the antioxidant system to neutralize hydrogen peroxide results in hydrogen peroxide reacting with superoxide to form the hydroxyl free radical. The hydroxyl free radical reacts with polyunsaturated fatty acids in biological membranes to form lipid peroxides. These lipid peroxides are the primary chemoattractants for inflammatory immune cells. Malondialdehyde is a biomarker of lipid peroxidation and thus represents and quantifies the oxidative stress load on biological systems. In order to assess the effect of elevating blood DHA-plasmalogens on the oxidative stress load on the participants in the trial, malondialdehyde levels, catalase and superoxide dismutase activity and C-reactive protein levels were measured in all participants at baseline and at the end of months 3-5. Although these biomarkers are quantitatively measured, they each have biological floor levels that represent a “healthy state” which cannot reasonably be improved upon. Accordingly, in addition to evaluating the effect of ProdromeNeuro on all participants, participants were also grouped into either low (Q1,Q2) or high (Q3,Q4) subgroups and evaluated accordingly.

ProdromeNeuro supplementation reduced malondialdehyde levels in all participants by 32% (p=0.028) and by 46% (p=0.002) in persons with high baseline malondialdehyde levels. Overall, malondialdehyde levels were negatively correlated with blood DHA-plasmalogen levels (r=-0.5, p=7.2e-07)

ProdromeNeuro supplementation increased catalase activity to 186% (p=0.014) of baseline levels in participants and to 240% (p=0.02) in persons with low baseline catalase activity. Overall, catalase activity was positively correlated with blood DHA-plasmalogen levels (r=0.28, p=0.008)

ProdromeNeuro supplementation increased superoxide dismutase activity (p=0.017) only in persons with low baseline superoxide dismutase activity.

Of the 22 participants, only 4 had baseline C-reactive protein levels greater than 1.0. All four of these participants had low baseline DHA-plasmalogen levels. All four of these participants exhibited a decrease in CRP by greater than 0.5 units and in two of the participants CRP levels decreased to less than 0.5.

The results of the oxidative stress biomarker analyses indicate that increasing blood DHA-plasmalogen levels using ProdromeNeuro has a profound positive effect on oxidative stress biomarkers.

ProdromeNeuro was well tolerated at all dosages and no adverse reactions were observed or reported.

The 26 remaining compounds decreased in dementia patients (P < 0.05) (Fig. 1 B–E). They consisted of four subgroups (B to E), having distinct characteristics. Group B compounds include ET and five other trimethyl-ammonium compounds. To our knowledge, except for ET (17), these are all not previously reported as dementia markers, probably because they are enriched in RBCs and scarcely studied in connection with dementia. ET is an antioxidant, a thiourea derivative of trimethyl-histidine. Two other ET-related, but less abundant, compounds, S-methyl-ET and trimethyl-histidine (hercynine), also declined strikingly in blood of dementia patients.

Group C compounds also decreased in dementia patients. These included ATP, NADP+ (oxidoreductive coenzyme), GSSG (redox compound), pantothenate (vitamin B5), S-adenosyl-methionine (SAM; methyl donor) (21), and gluconate (zinc carrier) (22). They are related to energy, redox reactions, methylation, and metal ions. Group C compounds were all enriched in RBCs, and four of the six are not previously reported as dementia markers. Two of them (SAM and GSSG) were previously shown to be AD-related (21, 23).

Trimethyl-tryptophan (hypaphorine), trimethyl-phenylalanine, glycerophosphocholine, dodecanoyl-carnitine (24), and trimethyl-tyrosine, all of which contain trimethyl-ammonium ions, also declined. The extent of reduction for trimethyl-tryptophan (0.10) and trimethyl-tyrosine (0.08) was striking. These reductions may be due to instability or reduced synthesis, or to reduced import in dementia patients. Of the nine compounds that contain a trimethyl-ammonium moiety, six of them that contain ET are enriched in RBCs and classified as group B compounds (Table 1).

Twelve group D metabolites (Table 1) are enriched in blood plasma and seven of them were previously reported to be dementia or AD markers. They include standard amino acids, glutamine (19, 25), phenylalanine (19, 26), tyrosine (19), histidine (19, 25), methionine, and tryptophan (regular amino acids) (18, 19), a pyrimidine nucleoside, uridine (27), and organic acids, 2-hydroxybutyrate (lipid-degradation product) and keto(iso)leucine (keto acid). Caffeine is a known dementia marker (28). Dimethyl-xanthine is a metabolite of caffeine. These greatly declined in dementia and are highly correlated with and isolated from other metabolites (see below) so they are designated as group E. Consistency of group D plasma metabolites as dementia markers but not group B and C RBC metabolites validated the method of searching dementia markers that we employed in the present study. The great majority of metabolites enriched in RBCs were not identified in the previous studies.

Nine trimethylated ammonium compounds were diminished in dementia patients.

Of nine trimethylated compounds that decreased in dementia, six are enriched in RBCs (SI Appendix, Fig. S2). Three of them (betaine, glycerophosphocholine, and dodecanoyl-carnitine) are present in plasma and are synthesized in the human body, whereas the other six, containing an aromatic moiety, are derived from food (29, 30). Most strikingly, six of these nine compounds are highly abundant (H, H-M, or H-L) in plasma and RBCs in healthy subjects, and are highly correlated so that their behavior may be highly coordinated. Hence, the sharp declines of these amphipathic compounds (possessing both hydrophilic and lipophilic properties and forming the basis of lipid polymorphism) in blood of dementia patients may strongly affect the physicochemical properties of neuronal systems.

Seven metabolites increased in dementia.

Interestingly, the seven metabolites of group A, comprising three nucleosides and four amino acid derivatives, increased in dementia (Fig. 1A). None was highly abundant and none was enriched in RBCs, and their increase in dementia occurred in plasma. Indoxyl-sulfate, kynurenine, and quinolinic acid (18) are involved in tryptophan metabolism and possibly act as excitatory toxins in the brain (31, 32), while N6-acetyl-lysine is implicated in histone and nonhistone protein modification (33). Pseudouridine, adenosine (19), and dimethyl-guanosine are degradation products of RNAs present in urine and are thought to be oxidized (34, 35). Increases of these metabolites in dementia are of great interest, as some are reportedly toxic in the central nervous system (CNS) and may lead to impairment of the brain (3638).

glymphatic waste clearance:

more on plasmalogens - Plasmalogens — MED-LIFE DISCOVERIES
Oral Supplementation of an Alkylglycerol Mix Comprising Different Alkyl Chains Effectively Modulates Multiple Endogenous Plasmalogen Species in Mice - PubMed

A study that looked at 2,252 adults aged 60 or older living in the US found that metabolic syndrome—defined as a combination of three or more symptoms, such as hyperglycemia, high blood pressure, or abdominal obesity—may hamper visual-spatial skills, attention, and processing speed. Participants with more features of metabolic syndrome performed worse on the test than others, with the most detrimental features being high blood glucose and blood pressure. In a study of 1,759 postmenopausal women in Denmark, high blood glucose levels and insulin resistance diminished verbal fluency, concentration, and memory. In Finland, a study that followed 3,695 adults aged 30-80 for more than a decade found that those with insulin resistance experienced the steepest declines in verbal fluency. Health records of 80,000 South Koreans aged over 60 revealed an 11 times higher chance of Alzheimer’s among people with metabolic syndrome.

Since insulin is so important in the brain, and severe insulin resistance underlies Type-2 diabetes, it follows that brain health worsens as diabetes sets in. Using data from more than 6,000 older adults who were part of the oft-cited Rotterdam cohort, one study found that diabetes almost doubles the risk of dementia. And a growing body of research suggests that diabetes significantly raises the risk of Alzheimer’s and more than doubles the risk of vascular dementia. A UK study of nearly 450,000 people aged between 40 and 69 looked at the relationship between blood glucose levels and the incidence of cognitive decline and dementia. People with prediabetic levels had 1.5 times the risk of vascular dementia compared to those whose blood sugar was in the normal range, and the risk was almost three times as much among those diagnosed with diabetes.

This result was backed up by a Spanish study that tested skills including verbal fluency and short-term memory in more than 1,800 adults with Type-2 diabetes and found that cognitive performance was better among patients who kept their blood glucose below a certain threshold. Evidence from Sweden has shown that dementia is diagnosed earlier in people with Type-2 diabetes, suggesting that young people with diabetes should be screened regularly to enable interventions that might delay cognitive decline.

photobiomodulation (could be an interesting intervention) esp at 40hz. MIT even published a few things on it

vielight also sticks the lgiht up the nose where it more easily accesses the regions (like EC) that the plaques and tangles of alzheimer’s disease first spreads from

vielight allows you to try them out for 180 days before returning