Heart disease is the leading cause of death. When discussing death from heart disease, heart disease and atherosclerotic heart disease are generally treated as the same thing and the terms used interchangeably. Atherosclerotic heart disease (ASHD), also called coronary artery disease and arteriosclerotic heart disease, is heart disease caused by decrease of blood supply due to narrowing of the coronary arteries. It's most dramatic manifestation is sudden death from acute myocardial infarction.
The first excellent description was in 1912 by American physician, James B. Herrick, who presented a paper entitled, "Clinical Features of Sudden Obstruction of the Coronary Arteries," which is now recognized as the classic description of a heart attack. Atherosclerotic heart disease and heart attack (acute myocardial infarction) have been well understood for past 100 years. At autopsy, death from acute heart attack and ASHD can be very well recognized with the naked eye. Obstructed coronary arteries are very clear and if there is prolonged survival, infarcted heart muscle is replaced by obvious fibrotic scar tissue.
Morbidity and death from heart failure is very common in the animal world; but atherosclerosis is uncommon. Atherosclerosis appears to only affect herbivores who eat an atherogenic diet. Dogs, cats, tigers and lions can be saturated with fat and cholesterol in their diet; but do not develop atherosclerotic plaques; yet they still can develop heart failure if live to old age. Carnivores have claws and sharp teeth. Humans resemble herbivores with a bad diet.
In the sections that follow, will review studies done on two animals, dogs and mice, that do not have atherosclerosis; but develop age-associated heart disease, similar to age-associated heart failure in humans.
Galen, a Greek physician and philosopher, who lived about 2000 years ago, put forth the idea that aging was not a disease; because everybody got aging and therefore aging was natural. Current dogma fully accepts this notion. Furthermore, traditional dogma states that people who die of natural causes, must die from a specific disease and since aging is not recognized as a disease, nobody can die from aging. In my opinion, this 2000 year old theory is long overdue to be relegated to the dustbin of history.
Another idea is that if something is a disease; then there might be a magic bullet to cure the disease; but if something is a natural process, then there can be no magic bullet.
In the following section, we will review a dog study and two mouse studies in which rapamycin did indeed act like a magic bullet. Short term (10-12 weeks) of rapamycin reversed age-related heart changes; the same pathology seen in humans in heart failure.
The point of this discussion, is that while atherosclerosis, hypertension, and diabetes can all cause heart disease; these is also intrinsic heart disease due to aging.
The focus of this section is intrinsic heart disease caused by aging, hereafter called age-associated cardiomyopathy, a disease not currently found in traditional textbooks of medicine.
Age-associated cardiomyopathy is a disease of mitochondria. The heart is packed full of mitochondria, constituting 30 percent of heart mass. Mitochondria produce the massive amount of energy the heart needs to pump blood.
Unlike coronary arteries, mitochondria can not be seen with the naked eye. They can only be visualized with an electron microscope. To elucidate age-associated cardiomyopathy requires a first class cardiac research laboratory and the ability to study the cardiac proteome. The cardiac proteome is all the proteins in the heart, about 800 different proteins. The study of changes in amounts of these proteins helps define the changes of age-associated cardiomyopathy.
While atherosclerotic heart disease has been understood and well recognized for the past 100 years, age-associated cardiomyopathy is only beginning to be defined in the research laboratory in the past 10 years.
Coronary artery disease is generally associated with pain. The temporary chest pain of angina and the severe crushing chest pain of acute myocardial infarction. In the 7th, 8th, 9th and 10th decades, age-associated cardiomyopathy commonly presents as exercise intolerance, shortness of breath on exertion. It can progress to congestive heart failure and death.
According to current statistics, out of a million older persons dying of heart disease; the ratio would be 1 million from ASHD and zero from age-associated cardiomyopathy.
My opinion, is that most older persons suffer from both age-associated cardiomyopathy and ASHD. For those without chest pain, age-associated cardiomyopathy is probably playing the larger role in their cardiac disease. However, both conditions contribute to the total risk of cardiac death and they are both fully competent killers acting either alone or acting together.
In summary: age-associated cardiomyopathy is not recognized to exist by traditional medicine for three reasons:
1. According to traditional thinking, aging is not a disease; therefore age-associated cardiomyopathy should not exist.
2. Age-associated cardiomyopathy is a disease of mitochondria and not seen with traditional autopsy.
3. Atherosclerotic cardiac disease is very common and thus serves as an overall diagnosis for all heart disease.
Nevertheless, age-associated cardiomyopathy is very real, very common and a major cause of cardiac morbidity and mortality.
Age-associated cardiomyopathy is mitochondrial heart disease as opposed to coronary artery heart disease.
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Silvan Urfer, Matt Kaeberlein, 2017, Seattle, Washington.
"In this study, 24 middle-aged healthy dogs received either a placebo or a non-immunosuppressive dose of rapamycin for 10 weeks. All dog received... echocardiography before and after the trial. Our results showed no clinical side-effects in the rapamycin-treated group compared to dogs receiving the placebo. Echocardiography suggested improvement in both diastolic and systolic age-related measures of heart function (E/A ratio, fractional shortening, and ejection fraction) in the rapamycin-treated dogs."
"Age is the single greates risk factor for nearly every major cause of morbidity an mortlity inhumans and their companion animals...Rapamycin is the drug that has shown the most robust and reproducible increase in lifespan and healthspan in laboratory mice.
"Treatment with rapamycin increases lifespan in evolutionarily divergent laboratory-organism including yeast, nematodes, fruit flies and mice. In addition to increasinglifespan, treatment with rapamycin has also been shown to improve a variety of age-associated conditions in mice, including cancer incidence, improving cognitive function, reversing cardiac and immune declines, restoring stem cell function and improving muscle function in aged animals."
We carried out a double-blinded clinical trial to assess dosing, safety and effects of rapamycin treatment for 10 weeks in healthy middle-aged companion dogs. Rapamycin treatment was either 0.05 or 0.1 mg/kg delivered orally 3 times per week.
All dogs were at least 6 years old and weighed 40 pounds. Dogs were very varied group with 12 mixed breed. They varied from 6.8 year old Doberman (lifespan 10-13 years to 10.4 year old Great Dane (life span 8-10 years) to oldest dog, mixed breed, 12.7 years.
8 dogs in control group, 5 in low rapamycin group, 11 in high rapamycin group.
Echocardiogram parameters:
Ejection Fraction (EF) Percent of the end-diastolic left ventricular blood volume that is ejected from the left ventricle during systol.
Fractonal Shortening (FS) Percent by which the left ventricular interior diameter is reduced at peak systole as compared to that of end-diastole.
E/ARatio: Ratio of early-to-late-diastolic velocity of blood flowing from the left atrium into the left ventricle.
Side effects: All clinical pathology blood tests remained normal.
Increased activity 70% (7/10) high rapamycin group and 40% (2/5) low rapamycin group.
Echocardiogram:
"Both the low and high dose rapamycin treatment group showed a trend toward improved fractional sshortening (FS) ejection fraction (EF) and E/A."
"Rapamycin significantly improved both FS as a measure of systolic function and the E/S ratio as a measure of diastolic function in rapamycin-treated dogs when compared to placebo.
Supplemental data showed high dose more effect than low dose.
Over 11 weeks, high rapamycin group showed marked improvement in all 3 measures, placebo group showed a marked deterioration in all 3 meaures and low dose rapamycin generally remained unchanged.
Effect on cardiac function
"Both systolic and diastolic function are know to deteriorate with age in dogs as well as in humans. Among these age-associated changes are reduced stroke volume and cardiac output as signs of systolic (through not necessarily accompaniedby a reduced EF), and a reduced E/A as a sign of diastolic dysfunction."
"There is evidence that rapamycin improves age-related deterioration of cardiac function in laboratory mice. Our study provides the first evidence that rapamycin may partially reverse age-related heart dysfunction in dogs by improving measures of both diastolic and systolic functions...All three outcomes (EF, FS and E/A ratio) showed trends toward improved function following rapamycin treatment and two of them (FS and E/A ratio) reached statistical significance.
"It appears that FS improvement was most prominent in rapamycin-treated dogs with lowever baseline values, while dogs that had higher values at baseline did not improve as much in response to rapamycin." This may suggest that degree of decline already present in each individual will determine degree of improvement. (greater initial decline, greater improvement).
Possible effects of rapamycin on behavior
Seventy percent (7/10) high dose rapamycin, owners reported dogs displayed increased activity and energy as did 40% (2/5) on lose dose.
25% (4/15) reported dogs behavior changed in a way they interpreted as more affectionate.
Conclusion: "Our resultsthus indicate that pharmacological inhibition of mTOR in older dogs likely has effects on heart function that are consistent with a reversal of age-related functional changes"
"to summarize, this initial study of rapamycin in healthy, middle-aged dogs showed that low-dose rapamycin treatment is safe over a period of 10 weeks and appears to recapitulate some of the beneficial effects that have been described for mTOR inhibition in mice... The absence of significant side effects here is consistent with findings from studies of marmosets in captivity
Flynn, 2013, Buck Institute, Calif.
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Results and Discussion:
"One of aging's molecular hallmarks is the presence of a sterile inflammation and cytokine production."
[ASG: Cytokines are a broad and loose category of small molecules that are important in cell signaling. They are produced by a broad range of cells. Cytokines have an effect on behavior of cell around them. They have great importance in health and disease. For discussion chronic inflammation and age-related disease see: Inflammatory Networks uring Cellular Senescense: Causes and Consequences. Freund, 2010]
"Sterile inflammation is defined as the presence of an immune response as a result of cellular damage from noninfectious sources."
"We sought to test whether rapamycin treatment reduces inflammation systemically in the sera and within aged heart tissue."
In sera (blood) evaluated 32 cytokines. 4 were significantly reduced from baseline with rapamycin treatment.
"To further investigate potential inflammation within the heart at the protein level, tested for 145 cytokines in cardiac tissue. 45 were significantly different between treated and control groups. ALL 45 were reduced in rapamycin treated group.
These data suggest that rapamycin treatment in the aged heart results in a suppression of the pro-inflammatory signaling which arises with age. Overall, our data suggest that ... the anti-inflammatory effects of rapamycin are more potent within cardiac tissue than systemically in the sera."
Discussion: "We determined that rapamycin was shown to significantly reduce the presence of specific inflammatory cytokines within the blood and more dramatically within the cardiac tissue. "One potential mechanism for the beneficial effects of rapamycin i mice may be the suppression of age-related inflammation...The release of pro-inflammatory cytokines from cardic cells has been demonstrated to promote fibrotic changes and hypertrophy, and therefore, a reduction in pro-inflammatory cytokines may prevent tissue damage both locally in the heart and systemically."
To determine the potential beneficial effects of rapamycin on cardiovascular function with 3 months rapamycin treatment in avanced age (>20 months of age), hearts evaluated with ultrasound imaging.
Control mice Rapa Mice
% ejection fraction 67-61 down 7.2% 63-69 up 8.5%
Weight heart 113 gm ---171 gm Up 51% 133 gm ---- 139 gm up 5%
The demonstrated a reversal of age-related cardiac dysfunction.
The rapamycin fed mice had significantly less cardiac hypertrophy over 3 months in advanced age.
"To further investigate the improvement in heart function, we carried out speckled-tracjing strain analysis of the echocardiogram data." [ a very sensitive test of cardiac function.
Results: Control mice showed slight decrease in whole wall function and in systolic and early diastolic strain rate in circumferential view.
Rapamycin treated mice showed significant improvement in both whole wall function and systolic and diastolic views.
Discussion: "Our results strikingly showed a functional improvement in ejection fraction and multiple other functional metrics with a reduction in hypertrophy of the heart over baseline levels prior to rapamycin treatment. These data showed a reversal of the typical progressive age-relate decline seen in C57BL/6J mice."
"Additionally, we observed improvement in the global peal strain and peak strain rates, a sensitive measure of myocardial systolic and diastolic function...Here we observed significant improvement in the circumferential orientation, which appear directly related to the net improvement in ejection fraction.
"Importantly, these same measures are used clinically and significantly decline with age or hypertrophy in patients. This result demonstrates for the first timerapamycin's ability to prevent loss of heartfunction in the context of the aging mouse."
"Because of the striking functional improvement in the heart compared with th other tissues examined, we performed detailed analysisof the molecular changes within cardiac tissue that arise due to rapamycin treatment in late life...We determined 700 genes differentially expressed in response to rapamycin treatment, with the majority, 521 downregulated..."The majority of upregulated genes upon rapamycin treatment are related to pathways involved in metabolic function and energy metabolism, consistent with related studie showing rapamycin enhances mitochondrial function."
The downregulated genes in categories related to immune function and inflammation. The data suggest that with age , there is increase in inflammatory processes known to be associated with aging. "Rapamycin attentuates the enhance cardiac inflammatory response."
One upregulated gene was PXR "whose signaling represses the inflamatory response through inhibition of the NF-KB pathway."
[ASG: NF-KB is major regular inflammation and and one of usual suspects in most age-related disease.]
Discussion:
The data showed anti-inflammatory effects. "However, reduced inflammation alone does not provide mechanistic explanation for the improved contractile function we observed via echocardiogram. To further investigate, examined a number of other classical markers within the heart tissue.
Cardiac hormone ANP was lowered after 3 months rapamycin treatment. Reduced ANP may prevent or dampen hypertrophic signaling.
analysis of expressed genes showed upregulation of heart disease-related protein RAD. Increased RAD "capable of both inhibiting hypertrophy and enhancing cardiomyocyte function by modulating calcium channels. RAD is suppressed in left ventricle of patients with end-stage heart failure and is linked to heart hypertrophy. "These data provide a potential linkage between rapamycin treatment and suppression of hypertrophy via enhanced levels of RAD and potentially explain the improved diastolic function observed."
Discussion: "the analysis of the remaining cardiac-related differentially expressed genes identified RAD as a potential modulator of cardiac function in the aged heart, which is a key protein in calcium signaling and has been linked to cardiac hypertrophy and heart failure. "We determined that RAD is indeed significantly upregulated with rapamycin treatment, which couldbe mechanistically linked with antihypertrophic and improvement in cardiac contractility. RAD functions in the cardiomyocyte related to calcium channels.
"Overall, these data support the hypothesis that rapamycin treatment improves excitation-contraction coupling in cells while simultaneously reducing endogenous stress signaling in the heart, resulting in preserved if not improved cardiac function with aging."
Dai, Rabinovitch, 2014, University of Washington, Seattle, Wa.
This is two part study regarding age-associated cardiomyopathy in aged mice.
One part of study is about reversal cardiac dysfunction with short-term caloric restriction or oral rapamycin. The second part of study is about changes in global cardiac proteome with same treatment. Cardiac proteome is all proteins in heart.
The study only included female mice. One control group was 4 month old mice fed regular diet. The other control group was 26 month old mice fed regular diet.
The study group was 26 month old mice kept on 40% caloric restriction for 10 weeks. The other study group was fed oral rapamycin for 10 weeks in same dose used in Harrison anti-aging mice study in 2009.
The first part of study was cardiac function in aged mice after 10 weeks on control diet, caloric restriction or rapamycin.
"At baseline, the aged heart phenotype in mice recapitulates the age-related changes of the human heart, including left ventricular hypertrophy and impairment of myocardial performance and diastolic dysfunction, as measured by echocardiography.
Left ventricular mass: Old mice fed with ad libitum control diet had an approximately twofold increase in left ventricular mass index compared to young controls indicating left ventricular hypertrophy. In both CR and rapamycin treated mice, echocardiogram showed reversal of age-dependent ventricular hypertrophy.
Fractional shortening (FS) did not significantly change with age or with treatment. (young, old and treated mice had same results)
Myocardial performance index (MPI) significantly worsened (increased) in old mice at baseline. CR or Rapamycin significantly improved the MPI in old heart when compared to control mice.
Diastolic function (E/A) significanly declined in old heart. While old mice have progressive decline of E/A after 10 weeks, treatent with CR or rapamycin significantly increased E/A. Treatment with rapamycin restored E/A to young mice level.
Discussion: "This study demonstrates that short-term, 10 week treatment with CR or rapamycin, initiated at old age, reverses many of the pre-existing functional deficits of cardiac aging, rather than just slowing down the aging process." TREATMENT WITH EITHER CR OF RAPAMYCIN FOR 10 WEEKS EFFECTIVELY REVERSES THE PREEXISTING CARDIAC HYPERTROPHY AND DIASTOLIC DYSFUNCTION.
[ASG note: Krebs cycle: (also called Citric acid cycle, TCA cycle, oxidaive phosphorylaton generated 38 molar ATP for oxidation ONE molecule of glucose.
Glycolysis: Generates 2 molecules of ATP
TCA cycle requires oxygen, takes place only in mitochondria.
Approximetly 15 times more efficient generating energy or ATP compared to glycolysis.]
Discussion:
"The proteome in the aged heart is notable for significant decline in proteins involved in mitochondrial function, ETC (electron transport chain) and fatty acid metabolism. Conversely, aged hearts have significant increased proteins in glycolysis/gluconeogenesis"
"This remodeling is similar to our previous observations in pressure-overload induced heart failure, including the decline in proteins in mitochondrial function, ETC and fatty acid oxidation and increase in proteins in glycolysis/gluconeogenesis pathways."
"This switch in preferential substrate utilization from more efficient fatty acid oxidation in the mitochondrial-rich normal heart to less efficient glycolysis/glucose oxidation in failing hearts has been extensively described in human and animals of heart failure"
"Although aged hearts do not demonstrate the full-blown phenotypes of end-stage heart failure, the concomitant changes in both functional performance and metabolic proteomes are obvious."
"The age-related decline in proteins in mitochondrial function, ETC ,and fatty acid metabolism is REVERSED by 10-week CR or rapamycin treatment."
[ASG note: The old heart switched to more inefficient glycolysis. CR and rapamycin restored use Citric acid cycle characteristic of healthy young hearts.]
[Discussion of Why:]
"As the increased mitochondrial protein abundance following CR and rapamycin occurred without increasing mitochondrial biognesis and mtDNA copy number, this suggests that the proteomic remodeling may be due to increaased abundance of these mitochondrial proteins that resulted from better preserved quality and slower turnover."
"These finding emphasize the crucial role of mitochondria in aging and are consistent with previous studies showing that preservation of mitochondria by overexpression of catalase targeted to mitochondria... attenuates age-dependent cardiomyopathy."
[ASG note: In previous study Dai showed that it preserved mitochondria by increasing mitochonria targeted catalase, which reduced ROS and apparent damage to mitochondria, this attenuated the development of age-associated cardiomyopathy. The implication is there is not increase in making more mitochondria or making more proteins associated with mitochondrial function; but rather the mitochondria and proteins are being better preserved.]
[Increase in fatty acid oxidation as fuel for TCA cycle]: "Rapamycin has been shown to reduce glycolysis and facilitate a switch in fat metabolism by increasing fatty acid oxidation in skeletal muscle...We confirm that rapamycin significantly reduces glycolytic metabolites and significantly increases TCA cycle metabolites in old mouse hearts. the increase TCA cycles metabolites despite the lower glycolytic intermediates suggest increased proportion of TCA cycle substrates coming from fatty acid oxidation. The concerted effect of rapamycin on these metabolic pathways are consistent with the changes in protein levels: increase in proteins involved in TCA cycle and fatty acid oxidation, and decrease in proteins involved in glycolysis."
Decreased protein damage: "Our study further shows that both CR and rapamycin decreased protein oxidative damage in the aged heart. [damaged proteins are removed by ubiquitination]
"This is consistent with the oberved decrease in protein ubiquitination, the rate-limiting step for the proteosomal degradation of oxidized proteins. Also consistent with this, CR and rapamycin decreased the proteomics turnover rate globally ( extended half-lives), and this is especially true for mitochondrial proteins."
"10 week CR or rapamycin results in improved protein quality and decreased protein damage, with resulting longer protein half-lives and reduced protein degradation. "
Loss of protein in old hearts: " It is noteworthy that the increased protein ubiquitination and trend toward increased carbonylation [oxidative damage to proteins, probably due to increased production ROS] in untreated old hearts are not accompanied by increased protein turnover (shorter half-lives) in old hearts; in fact, it trends toward slower turnover. This indicates that proteostasis is impaired in old hearts.
[ASG note: In old hearts proteins are damaged at increased rate and then removed. Porduction should increase to replace damaged proteins and maintain proper functional level; but production is not increased as shown by increased half-lives. Result is deficit of needed proteins, especially as needed for TCA cycle.
[The critical finding shown in Figure 5B (see paper)] "There were 327 proteins whose abundance was significantly changed. Proteins involved in mitochondrial dysfunction and ETC are significantly more abundant in YCL (young control) than in OCL (old control). indicating a decrease in these proteins with age." In rapamycin treated old mice the great majority of proteins of mitochondrial dysfunction and ETC, were restored to levels found in YCL (young control mice) to significantly reverse the aging difference.
This was not associated with an increase in mitochondria number.
Similar effects on proteome were seen in proteins invoved in fatty acid oxidation and TCA cycle pathways. (rapamycin restored to young profile)
YCL (young control) had significantly lower abundance of majority of proteins involved in gycolysis/glugoneogenesis, oxidative stress response.
Rapamycin effect: "The decrease in protein abundance in glycolysis together with the increase in abundance in fatty acid oxidation by rapamycin in old mice suggested that rapamycin shifts substrate utilization in old heart from glucose to fatty acid. ("similar to previous observation from skeletal muscle")
[See Fgure 6 A.B paper.Metabolic profiling]
Old rapamycin mice when compared to old control mice had significantly higher TCA cycle metabolites (a-ketoglutarate, fumarate, malate citrate) with ratios 1.32-1.41.
For glycolytic intermediates, old rapamycin mice had significantly lower ratio 0.45 (glucose-6-phosphate, fructose-6 phosphate).
This showed decreased in glycolysis and increase in TCA cycle in mitochondria, with increase in fatty acid oxidation.
Alterations in protein autophagy, ubiquitinaton and protein damage by rapamycin
No change in autophagy in cardiac aging.
"There was an increase in oxidative damage in old hearts, as shown by a higher of protein carbonylation (indicator oxidation). This increase is significantly reverse by rapamycin.
"The ubiquitin-proteosomal pathway is one of the major mechanisms for degradation of damaged proteins. Protein ubiquitination significantly increased in old control hearts aand this was significantly reversed by rapamycin. The reduction in protein damage and ubiquitination is consistent with the slower rate of protein turnover seen in rapamycin treated old hearts."
ABSTRACT
Caloric restriction (CR) and rapamycin inhibit mTOR. CR and rapamycin extends murine lifespan and ameliorate many age-associated disorders; however, the beneficial effects of shorter treatment on cardiac aging are not well understood. Usin a recently developed deuterated-leucine labeling method, we investigated the effects of short-term (10 weeks) CR or rapamycin on the proteomics turnover and remodeling of the aging mouse heart.
Functionally, we observed that short-term CR and rapamycin reversed the pre-existing age-dependent cardiac hypertrophy and diastolic dysfunction.
"There was no significant change in the cardiac global proteome (823) proteins) turnover with age, with a median half-life of 9.1 days in the 5 month-old hearts and 8.8 days in the 27-month-old hearts. However, proteome half-lives of old hearts significantly increased after short-term CR (30%) or rapamycin (12%). This was accompanied by attenuation of age-dependent protein oxidative damage and ubiquitination."
Quantitative proteomics and pathway analysis revealed an age-dependent decreased abundance of proteins involved in mitochondrial function, electron transport chanin, citric acid cycle and fatty acid metabolism as well as increased abundance of proteins involved in glycolysis and oxidative stress response."
"This age-dependent cardiac proteome remodeling was SIGNIFICANTLY REVERSE BY SHORT-TERM CR OR RAPAMYCIN, demonstrating a concordance with the beneficial effect on cardiac physiology."
Summary
"n summary, treatment with either CR or Rapamycin for 10 weeks in old mice effectively reverses the preexisting cardiac hypertrophy and diastolic dysfunction, attenuate age-dependent oxidative damage and ubiquitination, significantly decreases protein turnover, and ameliorates proteome remodeling in aging heart."
["Proteome remodeling" means all the age-related changes in proteins.]
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