Greetings everyone!

This is your host, Ralph Sanchez.

Today I am finally delivering on a preview note from my last episode in which I promised to provide an overview on what it takes to become a cognitive super-ager and truly live younger, longer.

Thus, I am very much looking forward to bringing you this review here today with regard to longevity and healthspan, and what more specifically underlies the capacity for anyone to attain a cognitive super-ager’s health and wellness lifespan (healthspan) if you think ahead.

The science of getting older (gerontology), and the biology of aging has spurred an immense interest and research effort that centers on the biochemical, molecular, and indeed the related senescent cellular changes that underlie age-related diseases.

And, the term "super-agers" has emerged as a handy expression to reference long-lived individuals that seem to weather the damaging brain aging processes associated with cognitive impairment. and retain a superior cognitive performance in later life.

According to study recently (2023) published in The Lancet Longevity Journal, super-agers are "people in their 80s who have the memory function of people 30 years younger".

So what is their secret?

Well, as all of you most likely know by now, numerous studies have asserted that the fundamental and healthy diet and lifestyle habits that nourish an optimal healthspan are requisite elements for life extension wellness and our brain health span.

Indeed, diet and lifestyle habits—that includes social enrichment—are often cited as keystone longevity pillars of long-lived centenarians of "Blue Zones"—5 or more specific regions around the world in which people achieve exceptional healthspans.

There is also a wealth of research that links a host of longevity genes to a longer lifespan and recent research indicates that genetic factors that influence longevity are particularly important the older you get (oldest old).

And, a number of studies have also determined that cognitively healthy centenarians are protected against Alzheimer's disease by a host of protective genes and their associated variants (genetic variants).

While the nature-nurture axis has some recognizable and potentially very modifiable pieces to the longevity puzzle, the science behind it all keeps revealing the secrets that not only allows for some fascinating insights, it also provides us all with a wellspring of knowledge which enables us, to some extent, to control our destiny.

One very important link that bridges the environment (nurture) to our innate potential (nature) is the emerging science of epigenetics—or the epigenetic modifications that are critical mechanisms in the dynamism of what I define as the “epigenetic bridge”.

Indeed, epigenetic mechanisms are a critical epigenetic bridge in upstream and core hallmarks of aging—dysregulation of epigenetic mechanisms (e.g., methylation, acetylation), accelerated telomere shortening and attrition, and genomic instability.

And those 3 hallmarks of aging all reflect the interrelated genomic and epigenomic determinants that are a critical component of accelerated aging processes.

However, there are 9 other hallmarks of aging that also must be taken into account when evaluating health assessments over the course of a healthspan.

Please listen in to this Cognitive Super-agers episode for the rest of story with regard to the hallmarks of brain aging, and how you can leverage that vital information for living younger, longer.

Fair warning … this review is lengthy and filled with the science backed research on epigenetic mechanisms and the Hallmarks of Aging.

Sincerely,

Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®
https://www.TheAlzheimersSolution.com

https://www.facebook.com/TheAlzheimersSolution/
https://www.linkedin.com/in/ralph-sanchez/


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Episode #22—Where We Left Off

I’ll begin this episode by sharing an excerpt of the primary outcome from study #1 that I reviewed in part #1—#22—of this two part episode series.

In that study, the authors found “a positive association between OC [plasma osteocalcin levels] and working memory capacity, executive functioning and global cognition scores.”

Study #2—Excerpt

The authors of study #2 remarked “we observed that in both older adults with osteopenia and older adults with AD [Alzheimer’s disease] as compared to cognitively normal participants, BMD [bone mass density] values were lower and were associated with the severity of cognitive impairments.”

And, "that BMD could identify AD participants with high accuracy”.

Study #3 —Excerpt

Bone loss biomarkers were analyzed, and a key DEXA scan (dual-energy X-ray ) finding from the study revealed that: a lower bone mineral density is closely associated with early-stage AD in male patients.

Study #4—Excerpt

In the review of study #4 of this two-part episode series, analysis of data drawn from 3,651 participants from a sub-study of the Rotterdam Study found that the participants that had a lower BMD [bone mineral density] had a twofold higher risk over those with a higher BMD of developing dementia.

Lastly, in episode #22, I quoted the lead author of the 2016 study, Christine Dengler-Crish, who stated “Measurement of bone density, which is routinely performed in the clinic, could serve as a useful biomarker for assessing AD risk in our aging population.”

Gut-Bone-Brain Axis—Excerpt

A significant body of research that has amassed over the past 20 years and more, and several key and recent studies have shown that the gut microbiota and the short-chain fatty acids (SCFAs), such as butyrate that are metabolized from fiber (resistant starches) fermentation play a role in regulating bone homeostasis (bone resorption and formation).

A very recent study concluded that “Our findings indicated that there were remarkable changes in gut bacteria, fungi, and fecal metabolites in postmenopausal women, and such changes were notably correlated with patients’ BMD (bone mass density) ​​and clinical findings.”

Estrogen in the Bone-Brain Axis—Excerpt

Estrogen—RANKL-RANK Pathway

I’ll now close out this episode with a review of a couple of key risk factors linked to estrogen, and how it all fits into the bone-brain axis.

A key pathway in which estrogen modulates bone remodeling is represented by a key regulatory factor in this bone remodeling phenomena—the receptor activator of Nf-kB—or its acronym—RANK.

Estrogen is a critical yin regulator of inflammation associated with osteoporosis and many other health conditions in a women’s body and brain.

Estrogen’s regulatory effect on inflammation—a yin force— counters and naturally buffers the inflammation pathway of RANKL and RANK—the yang element in this duality.

Tune in to hear the rest of the details and episode!

Thanks, and God Bless!

Ralph Sanchez, MTCM, CNS, D.Hom

BrainDefend®
www.TheAlzheimersSolution.com

https://www.facebook.com/TheAlzheimersSolution

https://www.linkedin.com/in/ralph-sanchez

https://www.instagram.com/alzheimers_solution

Hello once again!

This is your host Ralph Sanchez, and welcome to episode #22 and indeed, it has been much too long between this episode and the last one.

I have been busy with new book projects on the key underlying risk factors for late-onset Alzheimer’s disease that are unique to women.

I’ll have an announcement on when those books will be available here soon, and frankly, I'm looking forward to doing so.

And on that note, I have in store for you another special episode today in which I’ll present the evidence and the rationale for the bone-heart-brain axis as it pertains to an increased risk for dementia and late-onset Alzheimer’s disease (LOAD), and why age-related bone loss may be an indicator of an increased risk for LOAD.

Bone is an endocrine organ

Several key studies over the past 15 to 20 years have demonstrated that the human skeleton is an endocrine organ that bidirectionally communicates with our brain and our gut and other organs.

Normally, one may think of typical endocrine organs such as the pancreas, thyroid or pituitary gland which produce and release hormones that regulate a myriad of functions in the body and brain.

Well, the same can be said for bone, which secretes the hormones—FGF23 (Fibroblast growth factor-23) and osteocalcin—a peptide hormone.

So let's dive right in to that osteocalcin overview.

Osteocalcin—Heart and Brain Health

To begin with, a seminal study published in 2007 by Dr. Gerard Karsenty, has set in motion numerous studies since which have expanded on these endocrine and metabolic linkages between a form of osteocalcin—uncarboxylated osteocalcin (ucOC)—and other organs.

Indeed, bone cells (osteoblasts) secrete a form of a bone protein/hormone—osteocalcin (and others)—which is normally associated with the maintenance of bone mass, and it also functions as a key protein/hormone in the crosstalk and regulation of physiological pathways between bone

A modified form of osteocalcin, uncarboxylated osteocalcin (ucOC), easily crosses the blood brain barrier, and it has been shown to an essential hormone in fetal brain development, and in the regulation of mood and cognition throughout life.

Uncarboxylated osteocalcin that is associated with insulin resistance and cardiometabolic disease (metabolic syndrome, type 2 diabetes).

Uncarboxlated osteocalcin in turn regulates insulin secretion in pancreatic islet cells which underlies the regulation of glucose homeostasis by bone.

Thus, this bone-insulin dynamic is termed the bone-pancreas endocrine loop.

In a collaborative research effort and study published in 2017, Dr. Eric R. Kandel, a Nobel laureate (Nobel Prize for Physiology or Medicine in 2000) and senior researcher at Columbia University / Howard Hughes Medical Institute, and Dr. Karsenty, reported on a key hippocampal receptor— Gpr-158—that binds with osteocalcin and mediates hippocampal memory formation.

The study also reported another significant finding with regard to the benefit of how osteocalcin mediated “a molecular pathway critical for hippocampal-dependent memory” by stimulating brain-derived neurotrophic factor (BDNF) transport to the synapses of hippocampus.

So much more with regard to the role of osteocalcin and uncarboxylated in part 1 of this bone-heart-brain axis episode, so please listen in for the rest of the story.

Episode #2 of the Bone-Heart-Brain Axis will be available soon so please look for it as it will include additional insights into this fascinating and important research and science.

God bless and goodbye.


Ralph Sanchez, MTCM, CNS, D.Hom.

https://www.TheAlzheimersSolution.com

BrainDefend®

https://www.facebook.com/TheAlzheimersSolution/

https://www.linkedin.com/in/ralph-sanchez/

https://www.instagram.com

Welcome!

This is your host Ralph Sanchez, and this is episode #21, I am expanding on the last episode, #20, titled: “Estrogen Deficiency and Cardiometabolic Disease Underlies a Woman's Greater Risk for Alzheimer's Disease”.

This episode—part two of this two-part episode series—on the linkages between perimenopausal and postmenopausal estrogen declines in women and the risk for age-related disorders— will focus primarily on three types of estrogen:

• Endogenous estrogen (the kind you make).
• Estrogen replacement therapies (the kind you take), and
• Phytoestrogens (the kind you eat and supplement with),

and what they potentially represent in a woman’s risk for dementia and late-onset Alzheimer's disease (LOAD).

The role of endogenous estrogen is not often inserted into the discussion with regard to a woman’s risk for LOAD and it may be an important risk factor to weigh into a risk evaluation.

Note that today’s overview on the estrogen a woman naturally produces throughout her reproductive lifespan—endogenous estrogen—was not part of a previous episode, # 10, that focused on the importance of estrogen replacement therapy in women at midlife.

Plus, I’ll revisit estrogen replacement therapy (ERT) and some very important and more recent studies findings on that topic to be aware of, and how plant estrogens, or phytoestrogens, may substitute for ERT.

Since this will be a lengthy and dense overview on all of this here today, this summary will be a very abbreviated review of what I covered.

First, I’ll reiterate that the discussion and overview on postmenopausal estrogen deficiency as a risk factor for dementia and LOAD should not be a compartmentalized overview on estrogen’s role solely on neurological health.

As I detailed in the last episode, the role of estrogen in cardiometabolic health is a significant component that connects a woman’s vascular health, blood flow to the brain and atherosclerosis, in the risk for brain lesions known as white matter hyperintensities (WMHs).

And the brain damage associated with said brain lesions (WMHs) are a significant biomarker linked to the risk for cerebrovascular disease and stroke, vascular dementia, and LOAD.

Uncontrolled hypertension and atherosclerotic vascular disease restrict blood flow to the brain, and the vital nutrients and oxygen needed to fuel brain function.

Please listen in to episode #19 here in which I leverage recent studies on Viagra to make a point about several structure and function aspects of vascular health in aging individuals—both women and men—that are vital and modifiable risk factors for LOAD and vascular dementia.

Estrogen Exposure Throughout a Woman’s Lifetime

For decades, the research centered around the role of estrogen and estrogen replacement therapy in the risk for late-onset Alzheimer's disease (LOAD) has yielded conflicting results that ranged from:

• harmful, to
• no benefit to,
• protective.

In the last episode I explained why there is the seemingly conflicting outcomes that are associated with ERT, so please do listen in to that episode, #20.

Regardless, the preponderance of that research on estrogen therapy in the potential risk for LOAD has dealt with exogenous estrogen therapies.

However, there is another significant group of studies that must also be noted, and those are the ones that examined the link between the length of a woman’s reproductive years and the endogenous estrogen exposure during those years.

Endogenous Estrogen—Please listen in for the rest of this story!

Sincerely,

Ralph Sanchez, MTCM, CNS, D.Hom.

BrainDefend®
https://www.TheAlzheimersSolution.com

https://www.facebook.com/TheAlzheimersSolution/

https://www.linkedin.com/in/ralph-sanchez/

Welcome!

This is your host Ralph Sanchez, and this is episode #20 here at The Alzheimer's Solution Revolution podcast channel.

Today we are expanding on and diving a little deeper into two primary risk factors associated with an increased risk for dementia and late-onset Alzheimer's disease (LOAD) in women—cardiometabolic disease and postmenopausal estrogen deficiency in women.

In my book, and in episode #10 here on this channel, I covered the critical role that estrogen plays in glucose metabolism and its role in glucose hypometabolism.

In that episode I explain why glucose hypometabolism in the brain represents a neuroenergetic abnormality and risk factor for Alzheimer’s disease in aging individuals and how it pertains to postmenopausal women.

However, glucose hypometabolism is not the only metabolic derangement that links low estrogen levels to the higher incidence for LOAD in women.

The metabolic alterations related to type 2 diabetes, insulin resistance and cardiovascular disease is also linked to falling estrogen levels in perimenopause and postmenopause, which poses a significant risk for dementia and LOAD in women.

And if you are not aware of it, my book—The Diabetic Brain in Alzheimer's Disease— details the multifactorial role of cardiometabolic disease as a primary risk factor for vascular dementia and late-onset Alzheimer's disease (LOAD).

Indeed, in this episode—part 1 of this two-part episode series— we'll review the compelling research that describes pertinent and critical details with regard to the linkages between decreased estrogen levels after menopause and the increased risk for cardiometabolic disease in women.

In fact, apart from postmenopausal estrogen deficiency as a risk factor for LOAD, cardiometabolic disease is also a very significant risk factor associated with a woman's risk for vascular dementia and LOAD.

Regardless, the point today is that steep declines in estrogen in postmenopausal women is strongly associated with the risk for cardiometabolic disease and LOAD, and both factors ARE modifiable.

Cardiometabolic disease

The alarming rates of cardiometabolic disease worldwide and here in the U.S. (detailed in the podcast)

There also sex differences in the prevalence T2D and CVD across a lifespan.

The global prevalence of T2D and CVD before midlife is slightly higher in men compared to women.

However, there are regional and ethnic differences, and as men and women age, the prevalence of T2D and CVD (cardiometabolic disease) is markedly skewed toward a greater risk for both disease trajectories in women.

Before menopause, estrogen exerts a protective effect against CVD and T2D, whereas in postmenopausal women lower levels of estrogen and the loss of estrogen receptors leads to a precipitous decline in the protection against CVD and T2D in postmenopausal women.

And a number studies over the past years have found that compared to men, postmenopausal women have higher rates of cardiovascular complications associated with T2D.

Those cardiovascular complications include coronary heart disease or atherosclerotic cardiovascular disease, heart failure and stroke, and women have a higher mortality and worse prognosis after acute cardiovascular events.

It is also estimated that in women, over the next 3 to 4 decades (2025 to 2060), the prevalence of cardiometabolic disease and the complications just mentioned will continue to outpace men.

And again, to clarify the term cardiometabolic for those that are not familiar with it, it refers to metabolic health derangements that are linked to chroni

Summary

Hello and welcome to episode #19!

This is Ralph Sanchez and today I’ll be talking the outcomes of two recent studies that investigated the potential use of Viagra and Cialis in the risk reduction for late-onset Alzheimer’s disease (LOAD).

I was in part inspired to provide an overview on these two recent studies as they are cautionary tales on how many studies do not include the interrelated factors that are essential in arriving to an integrated assessment and analysis that serves their very premise— which is, does this or that work in a potential solution to something else?

Does Viagra or Cialis offer any proposed solution to the risk for LOAD and dementia?

Well today, I’ll be adding a great deal of information—the missing pieces to the puzzle as it were—with regard the pathways by which Viagra and Cialis may or may not work, and many other complimentary or natural alternatives that play a similar role in maintaining and optimizing a healthy cardiovascular and cerebrovascular system.

First, let me provide a little insight as to the molecular pathways in which drugs like Viagra and Cialis function, and why they may be considered as repurposed drug candidates for the treatment or in the risk reduction for LOAD.

Viagra (sildenafil) and Cialis (tadalafil) are Phosphodiesterase-5 inhibitors (PDE5is) which fall into a class of drugs that are normally prescribed to men to treat erectile dysfunction (ED), benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).

PDE5is can have a profound effect on cardiovascular health and PDE5is mediate their benefits by inhibiting the breakdown of a molecule, cyclic GMP (cyclic 3′,5′ guanosine monophosphate).

Cyclic GMP (cGMP) is an intracellular and second messenger molecule that modulates many downstream pathways, including significant effects in vasorelaxation—the ability of your blood vessels to dilate and expand as needed.

The vascular effect that is enabled by PDE5i-induced vasodilation is a pivotal pathway in vascular homeostasis and a healthy heart-brain axis.

And that vasodilation effect is how PDE5is improve and treat ED.

There is a lot more to that vasodilation benefit mediated by PDE5i therapy which I’ll get to here soon.

So on to a brief description of the two recent studies on Viagra and Cialis, and so much more that was not included in those studies that will provide a crucial insight into how you can improve your vascular health and reduce your risk for LOAD.

NIH Studies

First, a recent (2021)National Institutes of Health (NIH) funded study reported a risk reduction benefit of 69% for Alzheimer's disease (AD) in users of Viagra (Sildenafil).

The analysis simply compared Viagra users to those who did not take it, and the study was focused on a screen of drugs that could potentially be repurposed in the risk reduction for AD in aging individuals.

In a similar and second NIH funded study published this year (2022) titled— Drug Repurposing for Effective Alzheimer’s Medicines—(DREAM), the NIH analyzed data from Medicare beneficiaries that were treated with Viagra and Cialis.

The NIH team compared people with pulmonary arterial hypertension (PAH) treated with Viagra and Cialis over those with PAH on another class of drugs (endothelin receptor antagonists) used to treat pulmonary hypertension.

And note that PAH is a term that refers to high blood pressure in the blood vessels leading from the heart to the lungs

Yes, PDE5is are also prescribed to patients to reduce blood pressure in PAH, and off-label use of PDE5 inhibitors (PDE5is) is used to treat cardiovascular diseases, Raynaud’s disease and women with female sexual arousal disorder.

Summary

Welcome!

This is Ralph Sanchez and today I’ll be expanding on the last two episodes—#16 & #17—in this special brain detoxification series. This is the third or part three in that series.

In our last two brain detoxification episodes I described the pathways of beta-amyloid and tau protein transport and clearance from the brain, and in their degradation in the liver in what I describe as the liver-brain axis in Alzheimer’s disease.

Today I’ll provide an overview on two related and crucial mechanisms of clearing debris, eliminating pathogens and neurotoxic proteins within the neuron and brain—namely autophagy and a complimentary proteasome degradation pathway.

Autophagy

We’ll begin with autophagy which falters in aging and is significantly impaired in many age-related diseases such as cancer, cardiovascular disease, diabetes and neurodegenerative diseases such as Alzheimer's.

These age-related diseases directly impact cellular protein turnover and disposal which is largely dependent on autophagy and a proteasomal degradation pathway, termed the ubiquitin-proteasome pathway.

To keep this overview as simple as possible in light of the fact that all three forms of the autophagic machinery (macroautophagy, microautophagy, and chaperone-mediated autophagy ) and related pathways are very complex, I will for the most part only be describing here the role of macroautophagy with regard to the autophagy-lysosome pathway in waste recycling, removal and clearance.

Macroautophagy is the most studied and described type of autophagy and it is the very same one that most educators speak of when describing the role of dysfunctional autophagy in the risk for AD.

Now an important focus of today’s overview on autophagy is that it serves as an intracellular clearance mechanism of potentially toxic proteins such as beta-amyloid and tau protein that disrupt neuronal function and the integrity of our cognitive function in aging IF they are not appropriately turned over and degraded as needed.

Autophagy also mediates the degradation of pathogens (e.g., viruses, bacteria), the removal of damaged cellular organelles like the mitochondria, and the cellular removal and recycling of proteins derived from the degradation of these targets for a nutrient and energy supply.

The recycling of proteins and cellular organelles is a component in the regeneration of new proteins that serve as functional and structural substrates—e.g., cellular membranes and new organelles.

Indeed, autophagy is a vital mechanism in cellular homeostasis throughout our healthspan.

If your brain detoxification pathways are at their best, your odds of preventing dementia and living younger, longer are vastly improved.

Now much of the public awareness with regard to the role of beta-amyloid in the brain revolves around the notion that beta-amyloid protein eventually forms plaque—outside the neuron—in the extracellular environment.

And to that point, in the first episode (#16) of this brain detoxification series that focused on the transport and removal of beta-amyloid and tau protein from the brain, I gave an overview on the presence of beta-amyloid and tau protein in the extracellular fluid—the interstitial fluid—that is then funneled into the glymphatic system or transported across the blood brain barrier for removal from the brain.

Additionally, the amyloid precursor protein (APP) that traverses the membranes of the neuron and generates the very beta-amyloid peptides that can eventually aggregate into deposits in the extracellular environment is also present on membranes within the neuron.

APP is also present on mitochondrial membranes and the membranes of other intracellular organelles (e.g./ endoplas

Summary

Hello and welcome to episode #17!

This is Ralph Sanchez and today I’ll be expanding on the first episode’s overview with regard to beta-amyloid and tau protein clearance and detoxification.

If you did not catch that episode (#16), I provided an in-depth overview on the role of the blood brain barrier (BBB) and the glymphatic system in clearing and transporting toxic beta-amyloid and tau protein from the brain.

In today’s episode, I’ll review the emerging science and research with regard to the brain-liver axis in beta-amyloid clearance and metabolism, and how the gut fits into that, and a little on tau protein too.

Now, the peripheral metabolism of beta-amyloid in the body is a very complex overview, however, I will cover two important organs that are associated with the origin and degradation of beta-amyloid in the body—the gut and liver.

And, I will provide key features about that to illustrate what I term—the gut-brain-liver axis in late-onset Alzheimer’s disease (LOAD).

First, there are three points I will make here with regard to the gut-brain axis, and its potential role for a healthy brain, or for neurological disease such as Alzheimer’s and Parkinson’s disease.

• First, the gut is potentially a powerful vector for proinflammatory cascades that induce neuroinflammation responses.

• Secondly, alteration of the gut barrier integrity leads to similar loss of the blood brain barrier integrity,

• And lastly, the generation of beta-amyloid proteins produced by bacteria in the gut.

Yes, certain gut bacteria have been identified as specific beta-amyloid peptide producers linked to a beta-amyloid burden in the brain.

Now note the latter point I just made about gut-derived beta-amyloid-like peptides (proteins) generated by gut microbiota which I will elaborate on more here soon.

Nevertheless, the role gut-derived beta-amyloid-like proteins has in recent years been identified as drivers of neuroinflammation, AND amyloid and tau protein aggregation and deposition in the brain.

Of course, pro-inflammatory pathways are driven by a host of physiological and pathological mediators that includes the gut, and numerous chronic diseases such heart disease and diabetes (cardiometabolic disease) which is well-described in the research literature.

Gut-Brain Axis in Neuroinflammation

The role of the gut-brain axis is a significant factor in the risk for numerous health disorders throughout life, and it can have substantial implications on your body-brain health as you age.

Numerous studies that have examined the role of gut health disorders such as small intestine bacterial overgrowth or dybiosis to the detriment of brain health and the risk for cognitive decline and dementia have been accruing now for many years.

BTW, for those of you who have not run into the reference to gut dysbiosis, it simply refers to the altered gut ecosystem that is reflected by unhealthy imbalances of the gut microbiota.

And, as before, one significant driver of gut inflammation is the disordered ecological balance of the gut microbiota (dysbiosis).

Additionally, bacterial overgrowth patterns of dysbiotic bacteria are highly associated with elevations of a potent gut-brain toxin— lipopolysaccharides.

Lipopolysaccharides are bacterial surface molecules that are a major component of the outer membrane of Gram-negative bacteria.

Lipopolysaccharides are normally shed by gut bacteria, but in the case of microbiome imbalances associated with bacterial overgrowth patterns (dysbiosis), a proliferation of dysbyotic bacteria—the bad guys, too much pro-inflammatory lipopolysaccharide matter is shed into the gut and peripheral circulation which can lead to powerful systemic toxic and inflammation reactions.

With regard to the central n