Contrasting Myocardial Aging and Healthspan

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Questions and Answers

What effect does Dapagliflozin have on hospitalization for cardiovascular diseases?

It reduces hospitalization rates. (correct)

It has no effect on hospitalization rates.

It causes hospitalization for additional diseases.

It increases hospitalization rates.

In addition to reducing oxidative stress, how does Dapagliflozin help cardiac function?

By enhancing the production of harmful oxidative species.

By increasing the burden of oxidative stress.

By activating the AMPK/NAMPT/SIRT pathway. (correct)

By inhibiting the antioxidant defenses.

What is the relationship between Dapagliflozin and skeletal muscle weakness?

Dapagliflozin solely treats muscle conditions.

Dapagliflozin has no impact on muscle weakness.

Dapagliflozin can improve skeletal muscle weakness. (correct)

Dapagliflozin worsens skeletal muscle weakness.

What is one of the targets of new treatments that includes Dapagliflozin?

Fibrosis. Signup and view all the answers

Which pathway does Dapagliflozin activate that is associated with stress-induced premature senescence?

SIRT1 pathway. Signup and view all the answers

How do senescent cells affect neighboring cells?

They spread the 'sickness' through associated phenotypes. Signup and view all the answers

What role do sirtuins play in organisms, according to the provided content?

They regulate health span and lifespan. Signup and view all the answers

Which of the following statements about the action of Dapagliflozin in type 2 diabetes is true?

It alleviates pathological aging through SGLT2 inhibition. Signup and view all the answers

What is the main mechanism of action of dasatinib?

Inhibiting cell proliferation Signup and view all the answers

Which of the following conditions has shown improvement through the combination of dasatinib and quercetin (D+Q) in mice?

Aging-related frailty Signup and view all the answers

What is the primary characteristic of the senescence-associated secretory phenotype (SASP)?

It secretes pro-inflammatory molecules. Signup and view all the answers

What role do senostatics play in senotherapy?

They suppress harmful effects of senescent cells. Signup and view all the answers

Which signaling pathway is involved in juxtacrine senescence?

NOTCH1-JAG1 pathway Signup and view all the answers

Which signaling pathway is NOT mentioned as being targeted by senostatics?

PI3K Signup and view all the answers

How do senescent cells contribute to tissue dysfunction?

By continuously secreting harmful factors. Signup and view all the answers

What is a potential effect of rapamycin in relation to senolytic therapy?

Reducing the SASP Signup and view all the answers

In which of the following conditions is D+Q being tested in human clinical trials?

Alzheimer’s disease Signup and view all the answers

What potential benefit does cellular senescence provide?

Prevents the proliferation of damaged cells. Signup and view all the answers

What is the primary purpose of targeting the SASP in senotherapy?

To mitigate detrimental impacts of senescent cells Signup and view all the answers

What effect does the composition of SASP have on age-related diseases?

It can enhance the risk of age-related diseases. Signup and view all the answers

Why is the persistence of senescent cells problematic?

They secrete factors that damage surrounding tissues. Signup and view all the answers

Which of the following statements about quercetin is true?

It naturally occurs as a flavonoid. Signup and view all the answers

What happens to the efficiency of the immune system in clearing senescent cells as we age?

It decreases substantially. Signup and view all the answers

What is a common characteristic of the SASP factors?

They can include a range of cytokines and chemokines. Signup and view all the answers

What is a primary visual indicator of cellular senescence?

Flattened and irregular cell shape Signup and view all the answers

Which enzyme is primarily responsible for the hallmark activity in senescent cells?

β-galactosidase Signup and view all the answers

What substrate is commonly used to detect SA-β-gal activity?

X-gal Signup and view all the answers

Which gene is overexpressed in senescent cells related to SA-β-gal activity?

GLB1 Signup and view all the answers

What characteristic change occurs to the cytoplasm of senescent cells?

Increased granular structures Signup and view all the answers

What does the blue staining produced from X-gal indicate?

High SA-β-gal activity Signup and view all the answers

Which of the following best describes a feature of senescent cells?

They show an upregulation of lysosomal enzymes. Signup and view all the answers

What does the term 'senescent cells' primarily refer to?

Cells that have become dysfunctional and stop dividing. Signup and view all the answers

What is one of the primary mechanisms through which metformin lowers blood sugar levels?

Inhibiting hepatic gluconeogenesis Signup and view all the answers

Which of the following properties of metformin helps prevent blood clots?

Anticoagulant and fibrinolytic properties Signup and view all the answers

How does metformin affect AMP levels in the body?

It increases AMP levels by reducing ATP production Signup and view all the answers

Which transcription factor is inhibited by increased AMP levels as a result of metformin use?

CBP Signup and view all the answers

What cellular component does metformin specifically target to exert its effects?

Mitochondria Signup and view all the answers

In addition to lowering blood sugar levels, metformin has been shown to down-regulate which type of biological markers?

Senescence markers and SASP factors Signup and view all the answers

What effect has metformin been shown to have on the lifespan of model organisms?

It increases lifespan independent of diabetes effects Signup and view all the answers

What is one of the lipid metabolism effects of metformin?

Lowers triglycerides and LDL cholesterol Signup and view all the answers

What was the initial purpose of rapamycin before its other applications were discovered?

As an anti-fungal agent Signup and view all the answers

Which complex does rapamycin specifically inhibit?

TORC1 Signup and view all the answers

How does resveratrol help maintain cell function in endothelial progenitor cells?

By activating telomerase through the PI3K-Akt pathway Signup and view all the answers

Which of the following is NOT a mechanism of action associated with rapamycin?

Activating SIRT1 Signup and view all the answers

What potential benefit does metformin offer beyond its use for type 2 diabetes?

It reduces cellular SA-β-gal activity Signup and view all the answers

What effect does rapamycin have on lifespan when administered late in life in mice?

It extends both median and maximum lifespan Signup and view all the answers

Which compound functions similarly to caloric restriction by activating sirtuins?

Resveratrol Signup and view all the answers

Which pathway does resveratrol block to suppress SASP factors in human bone marrow stromal stem cells?

NF-κB pathway Signup and view all the answers

What has contributed to the change in life expectancy over the past century?

Medical and technological innovations Signup and view all the answers

What does the term 'healthspan' refer to?

The years lived without chronic diseases Signup and view all the answers

What are competing risks in the context of aging populations?

Increased risk of death from non-infectious diseases Signup and view all the answers

How does the improvement in life expectancy appear to be changing?

Lifespan improvements have plateaued Signup and view all the answers

What potential benefit is expected to emerge around 2030 in regard to healthspan?

A better alignment of life expectancy and healthspan Signup and view all the answers

Which of the following diseases is notably prominent in aging populations?

Heart failure Signup and view all the answers

What has primarily been the leading cause of death historically, prior to the emergence of new diseases?

Infectious diseases Signup and view all the answers

What is a major risk factor for heart failure and cardiovascular disease?

Age Signup and view all the answers

What is the primary reason for using FISCHER (CDF) rats in aging studies?

They are the main aged rodent colonies used to study aging. Signup and view all the answers

Which drug combination was found to have unexpected inefficacy to improve diastolic function in the studied mice?

Sacubitril and Valsartan Signup and view all the answers

What is a notable attribute of Dapagliflozin regarding its approval?

It was initially approved as a diabetic drug. Signup and view all the answers

What significant change was made in the treatment regimen for the CDF rats?

The drugs were administered at an earlier age. Signup and view all the answers

Which cardiovascular effect was indicated for Rosiglitazone after its approval as a diabetic drug?

Cardiotoxicity was discovered. Signup and view all the answers

What compound was combined with Sacubitril and Valsartan in the experimental set for old mice?

Dapagliflozin Signup and view all the answers

In which scenario was hemodynamic and echocardiographic analysis performed?

After the treatment had been extended to 10 months. Signup and view all the answers

How were the CDF rats categorized in the study?

By treatment type. Signup and view all the answers

What is a characteristic feature of senescent cells identified through cytological methods?

Presence of senescence-associated ß-galactosidase Signup and view all the answers

Which of the following markers is typically associated with the detection of senescent cells?

Lipofuscin accumulation Signup and view all the answers

What is the focus of Phase II in the study of senescence?

Determining the subtype of senescence present Signup and view all the answers

Which proteins are part of the senescence-associated secretory phenotype (SASP)?

Pro-inflammatory cytokines and secreted proteins Signup and view all the answers

Which genes are known to be upregulated in senescent cells?

p16, p21, and lamin B1 Signup and view all the answers

What signifies Phase III in cell culture?

Cessation of replication but continuing metabolism Signup and view all the answers

What is a common effect of the SASP on surrounding tissues?

Induction of a pro-inflammatory environment Signup and view all the answers

Why is identifying senescence subtype-specific transcripts important?

To evaluate their effects on disease progression and treatment Signup and view all the answers

What type of senescence involves the secretion of pro-inflammatory molecules that affect nearby cells?

Paracrine senescence Signup and view all the answers

Which pathway is specifically associated with juxtacrine senescence?

NOTCH1-JAG1 pathway Signup and view all the answers

What is a potential consequence of the senescence-associated secretory phenotype (SASP)?

Inducing senescence in adjacent healthy cells Signup and view all the answers

What allows senescent cells to avoid self-destruction?

Activation of anti-apoptotic pathways Signup and view all the answers

Why might the absence of common SASP markers not rule out senescence?

The composition of SASP varies depending on the cell type and tissue. Signup and view all the answers

What is a detrimental effect associated with the accumulation of senescent cells as we age?

Increased risk of age-related diseases Signup and view all the answers

Which of the following accurately describes a consequence of tissue dysfunction linked to senescent cells?

Worsening tissue damage over time Signup and view all the answers

What does senescence-associated secretory phenotype (SASP) typically NOT promote?

Cellular recovery Signup and view all the answers

What is the primary aim of senolytic therapy?

To eliminate senescent cells through programmed cell death Signup and view all the answers

What is a potential risk associated with targeting senescent cells?

Disruption of tissue repair and wound healing Signup and view all the answers

Which approach focuses on modulating the effects of senescent cells without their elimination?

Senomorphic therapy Signup and view all the answers

Which drug combination is among the earliest identified senolytic therapies?

Dasatinib and quercetin Signup and view all the answers

What does the Threshold Theory of Senescent Cell Accumulation propose?

Once a threshold is surpassed, senescence spreads to neighboring cells Signup and view all the answers

What phenomenon does SASP stand for in the context of senescent cells?

Senescence-Associated Secretory Phenotype Signup and view all the answers

What do senolytic interventions aim to achieve for age-related diseases?

They help delay or prevent age-related diseases Signup and view all the answers

What is a self-perpetuating cycle in the context of senescent cells as described in the content?

Accumulation of senescent cells triggers SASP, spreading senescence faster than clearance Signup and view all the answers

What is the primary mechanism of action for dasatinib in cancer treatment?

Blocking tyrosine kinase activity Signup and view all the answers

Which senolytic therapy has shown promise in treating age-related conditions in mice?

Dasatinib and Quercetin (D+Q) Signup and view all the answers

What is a significant benefit of using senostatics in therapy?

They target signaling pathways without removing senescent cells. Signup and view all the answers

Which pathway is NOT involved in the senescence-associated secretory phenotype (SASP)?

Wnt signaling Signup and view all the answers

What condition is NOT listed as being tested for D+Q in human clinical trials?

Type 2 diabetes Signup and view all the answers

Which biological activity is associated with quercetin?

Interacting with Bcl-2 proteins Signup and view all the answers

What effect does rapamycin have on the SASP?

It reduces the secretion of harmful SASP molecules. Signup and view all the answers

Which of the following best describes the purpose of senotherapy?

To reduce the negative effects of senescent cells. Signup and view all the answers

Study Notes

Contrasting Myocardial Aging: From Mice to Men

Life expectancy globally is ~73.3 years.
Death distribution data from 1900 and 2016 show a shift in longevity.
Technological advancements in medicine are increasing healthspan.
Competing risks arise as death risks from one disease decrease, others increase (e.g., infectious to chronic).
Maximum human lifespan extension is unlikely in this century.
Life expectancy is increasing, but the rate is slowing.
Healthspan is ~64 years, a 9.2-year gap from life expectancy.

Hallmarks of Aging

Mitochondrial dysfunction
Pro-inflammatory signaling
Nutrient sensing dysregulation
Oxidative stress
Loss of proteostasis
Epigenetic alterations
Genomic instability

Heart Failure in Aging

Heart failure is a significant aging-related disease.
Age is a major risk factor for heart failure and cardiovascular disease.
Cardiac dysfunction involves multiple processes including fibrosis, inflammation, diastolic dysfunction, mitochondrial dysfunction, and apoptosis.

Research Models

Fischer (CDF) rats are aged rodent models.
A specific mouse subgroup (C57BL/6 +HFD +DOCP) is frequently used in aging, hypertension, and cardiometabolic studies.
Mice were treated with drugs (like Sacubitril or Valsartan) to evaluate heart failure treatment efficacy across different aging stages.
Treatment duration and treatment initiation age were adjusted to improve research outcome.

Senescence

Replicative senescence occurs as cells divide repeatedly, shortening telomeres, inducing cell cycle arrest.
Senescence is a permanent state of growth arrest triggered by stressors and replicative limitations.
Cellular senescence can also be induced by various physiological states, including replicative senescence, physiological processes, and premature senescence.
Cellular senescence is regulated by multiple pathways, including DNA repair, telomere maintenance, and others.
Senescent cells secrete SASP factors, causing inflammation and tissue damage that can accelerate aging.
Markers for cellular senescence include SA-ẞ-gal activity, lipofuscin accumulation, and senescence-specific gene expression signatures.

Senescent Cell Detection

Several methods are used for detection, including SA-β-gal staining, lipofuscin detection (GL13), and analysis of proliferation markers (EdU and Ki67).
Combining these approaches allows researchers to ensure accurate identification of senescent cells.

Senotherapy

Senolytic therapies aim to eliminate senescent cells.
Senomorphic therapies aim to modulate the senescence-associated secretory phenotype (SASP).
Senescent cell accumulation above a certain threshold can trigger a negative feedback loop accelerating aging and chronic disorders.

Metformin in Aging

Metformin, an antidiabetic drug, can potentially ameliorate the adverse effects of aging by lowering blood sugar levels.
It can suppress cellular senescence by affecting cellular processes, such as increasing AMPK activity, reducing oxidative stress, and enhancing autophagy.
Metformin may extend lifespan and healthspan.

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Description

This quiz explores the impact of aging on myocardial health, highlighting the differences in lifespan and healthspan amongst humans and animal models. It addresses the hallmarks of aging, heart failure, and the effects of age on cardiovascular diseases. Test your understanding of these critical topics in aging and cardiovascular health.