aging – The Early Career Voice

Join the race against the clock: Controlling for age in cardiovascular disease

May 18, 2022May 16, 2022 Melody Chemaly, PhD

The race against aging has already started. People who want part of this race see the limitless opportunities humans will have if aging is taken out of the equation. Humans will be able to live longer with their loved ones, go back to University when they are 70 years old to study this long-dreamed profession they always wanted to try or take the time to go through every single item on their bucket list, no matter how long the list is. Others are worried about what awaits them at the finish line of the race and what sacrifices will have to be made along the way. They argue that aging is the core of our existence and the reason why we make the choices we make every day. If humans don’t age, will they still find a reason to live and would this type of life be worth living? Regardless of people’s scattered opinions, the remaining question to be answered in our race against the clock is: Can we age disease-free?

As humans began to live longer dying less of problems such as hunger, wars and infections, they were faced with a new type of problem: chronic diseases. As we age and get exposed to different environmental and lifestyle factors, a set of biological and functional changes in our bodies lead to the development of chronic diseases such as cardiovascular diseases (CVD), diabetes, cancer, dementia, arthritis, and the list goes on. Notorious for being the ‘number 1 killer in the world’, preventing CVD has been one of the top priorities in our fight against aging. Age is the best predictor of CVD death, and despite years of research and large amounts of funding spent on biomarker discovery, there are currently no better predictors of CVD death than the age of a person and these are some of the reasons why.

Large blood vessels tend to become stiffer over time as they accumulate more collagen (due to an increase in TGF-b activity leading to collagen synthesis from smooth muscle cells) and lose their elastin content (because of higher metalloproteases and cathepsin activity). This leads to a chronic increase in systolic blood pressure which is worsened by the rise of catecholamines levels usually seen during aging. Both phenomena contribute to left ventricular dysfunction and hypertrophy due to the increase in myocardial oxygen demand. Calcification is another hallmark of aging that also contributes to vessel stiffness and induces stenosis. As we age, skeletal calcium is released and tends to accumulate in the vascular structures.

Apart from leading to vessel stiffness, aging causes the vascular endothelial cell (EC) barrier to become dysfunctional. ECs play a crucial role in maintaining vessel integrity and homeostasis by balancing vasodilatory and vasoconstricting functions and by aligning the vessels with an anti-thrombotic surface. Disruption of this protective barrier over time is characterized by ECs undergoing oxidative stress, reduced nitric oxide (a potent vasodilator) production, increased expression of adhesion molecules (ICAM and VCAM) and secretion of inflammatory chemokines (CXCL8) and cytokines (IL-1b and IL-6). The initiating event of atherosclerosis development starts with endothelial dysfunction which gives way for monocyte infiltration and subsequent foam cell formation contributing to plaque development.

At the molecular level, changes affecting the genome and epigenome are a fundamental feature of aging. With age, the clonal diversity of hematopoietic stem cells decreases resulting in the predominance of one clone. In recent years, clonal hematopoiesis of indeterminate potential (CHIP), which occurs as a result of mutations in transcriptional regulators (DNMT3A, TET2 and ASXL1), was found as a novel CVD risk factor, thereby linking genetic mutations in hematopoietic stem cells, aging and CVD. The number of endothelial progenitor cells also decreases over time which reduces angiogenesis capacity and capillary density leading to microvascular disease (such as peripheral artery disease).

The shortening of chromosome telomers is another molecular change related to aging. As cells replicate, telomeres get shorter until cellular senescence is triggered. Cellular senescence is a cellular protective mechanism that activates NK cells to remove cells with defective genetic material via apoptosis. It has been shown that patients with reduced leukocyte telomere length have increased risk of atherosclerosis. An atherosclerotic plaque, rich in inflammatory cells and trans-differentiated smooth muscle cells, is a dense hypoxic environment characterized by the presence of reactive oxygen species which also induce DNA damage and senescence.

Current therapies for atherosclerosis target some of the pathways of aging highlighted above. While statins are known to reduce plaque lipid content and inflammation, in parallel, they tend to increase calcification leading to vascular stiffness. On the other hand, anti-hypertensive treatments offer benefits beyond reducing CVD mortality, but also decreasing dementia. Recently, novel therapies targeting aging in CVD have focused on stem cell therapy. However, clinical trials using cell therapy to improve left ventricular dysfunction or to reduce cardiovascular events have shown no or modest benefit. This may be because autologous cell therapy of stem cells that already have an ‘aging’ phenotype is not ideal, and these cells may require ex vivo reprograming to improve treatment efficiency.

Since many age-related diseases have similar underlying molecular mechanisms driving them, the future for treating chronic diseases will rely on targeting the mechanisms of aging rather than treating the disease itself. Some of the best ways to slow down aging is by being active, controlling blood glucose levels, opting for diets rich in antioxidants and fibers and introducing low calorie intake periods during the day. However, this usually requires a substantial effort and serious lifestyle changes on our behalf. But, since research on anti-aging therapies and senolytic drugs is booming, it might be possible to slow down aging by taking one or two pills a day without ever needing to change the routines that we are so comfortable with.

References

Paneni F, Diaz Cañestro C, Libby P, Lüscher TF, Camici GG. The Aging Cardiovascular System: Understanding It at the Cellular and Clinical Levels. J Am Coll Cardiol. 2017 Apr 18;69(15):1952–67.
Quyyumi AA, Vasquez A, Kereiakes DJ, Klapholz M, Schaer GL, Abdel-Latif A, et al. PreSERVE-AMI. Circ Res. 2017 Jan 20;120(2):324–31.
Brouilette SW, Moore JS, McMahon AD, Thompson JR, Ford I, Shepherd J, et al. Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study. The Lancet. 2007 Jan 13;369(9556):107–14.
Koopman JJE, Kuipers RS. From arterial ageing to cardiovascular disease. The Lancet. 2017 Apr 29;389(10080):1676–8.
Jaiswal S, Libby P. Clonal haematopoiesis: connecting ageing and inflammation in cardiovascular disease. Nat Rev Cardiol. 2020 Mar;17(3):137–44.
Antonangeli F, Zingoni A, Soriani A, Santoni A. Senescent cells: Living or dying is a matter of NK cells. J Leukoc Biol. 2019 Jun;105(6):1275–83.
What is the Age of My Heart? – Calculate Your Own Heart Age • MyHeart [Internet]. MyHeart. 2015 [cited 2022 May 16]. Available from: https://myheart.net/articles/what-is-the-age-of-my-heart-calculate-your-own-heart-age/

“The views, opinions, and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness, and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions, or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your health matters. If you think you are having a heart attack, stroke, or another emergency, please call 911 immediately.”

How to Protect Your Aging Heart

November 14, 2021November 14, 2021 Huan Wang, PhD

“Man is as old as his arteries.” –Thomas Sydenham

Cardiovascular diseases are commonly associated with unhealthy lifestyles. Do you know that age is a strong predictor of cardiovascular diseases in both men and women? As you grow older, your risks of suffering a heart attack, to have a stroke, or to develop coronary heart disease and heart failure are getting much higher. Ageing research has been evolving rapidly in the recent decades. In the early days, ageing research was mostly focused on Alzheimer’s disease and related dementias. To improve quality of life in ageing population, other symptoms of ageing including physiological function decline start to capture scientific community’s attention. In AHA Scientific Sessions 2021, a panel of experts and professionals in the field talked about novel strategies to promote healthy vascular aging.

To prevent cardiovascular diseases in aging populations, there are many take-home messages from today’s live session. Dr. Blumenthal from Johns Hopkins University used a simple “ABCDEF” approach¹ to highlight the most recent development in cardiovascular diseases management based on most recent scientific discoveries and epidemiological results. Two of the major factors: Diet and Exercise, which are closely associated with body weight management, are further elaborated by Drs. Willett and Donato, respectively.

Dr. Willett is a professor of Epidemiology and Nutrition from Harvard Medical School. He challenged the recommendation of Dietary Guidelines for Americans (DGA). Dr. Willett encouraged the public to focus on evidence-based dietary recommendation, and to evaluate epidemiological studies by using randomized control trials with risk factor, disease incidence and mortality outcomes and prospective epidemiological studies with equal intensity intervention of 12-month and longer. Aside from canonical discussion of dietary recommendation based on health benefits, Dr. Willett raised a pertinent point in environmental sustainability. “How to feed 2 billion people in 2050?” he asked. Climate change is a global crisis and agriculture plays a pivotal role in fighting it. In “the Omnivore’s Dilemma”, Michael Pollan talked about how livestock production is responsible for much of the carbon footprint of global agriculture. The best practice for specific diets to prolong healthy life needs to take into consideration of reducing carbon footprint.

Vascular ageing is comprised of multiple processes including cellular senescence, inflammation and oxidative stress². Dr. Donato talked about how ageing affects endothelial cell function and habitual aerobic exercise improves endothelial function in men. He also raised an interesting point: this beneficial effect of exercise on endothelial function is sex dependent. More research on sex differences needs to help us understand how to promote healthy ageing. DNA damage is associated with vascular aging. Dr. Shanahan discussed the signaling pathways involving in DNA damage and cellular senescence-associated phenotypes on vascular calcification. Inhibition of DNA damage agents can mediate vascular calcification progression. Can we use DNA damage as a biomarker to detect vascular ageing?

The “One-size-fits-for-all” approach in disease prevention and treatment requires a new perspective. In 2015, Precision Medicine Initiative was launched to accelerate research in disease treatment and prevention by considering individual differences in people’s genes, environments and lifestyles. With the development of next-generation sequencing, risk factors for coronary artery diseases require a modification. Dr. Wolford discussed her research on incorporating genetic backgrounds for disease prediction using polygenic risk scores³. It’s only the beginning of an exciting era using precision medicine as a tool for disease prevention and intervention in cardiovascular diseases.

To protect an aging heart, many approaches need to be implemented. Healthy lifestyles, nice environment and consideration of individual differences are all part of a clue.

REFERENCE

Feldman DI, Wu KC, Hays AG, Marvel FA, Martin SS, Blumenthal RS, Sharma G. The Johns Hopkins Ciccarone Center’s expanded ‘ABC’s approach to highlight 2020 updates in cardiovascular disease prevention. American Journal of Preventive Cardiology. 2021;6:100181.
Donato AJ, Machin DR, Lesniewski LA. Mechanisms of Dysfunction in the Aging Vasculature and Role in Age-Related Disease. Circulation Research. 2018;123(7):825–848.
Wolford BN, Surakka I, Graham SE, Nielsen JB, Zhou W, Gabrielsen ME, Skogholt AH, Brumpton BM, Douville N, Hornsby WE, Fritsche LG, Boehnke M, Lee S, Kang HM, Hveem K, et al. Utility of family history in disease prediction in the era of polygenic scores. medRxiv. 2021:2021.06.25.21259158.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

A Few New Thoughts on the Road to Younger Arteries

November 13, 2021November 13, 2021 Kyla Lara-Breitinger, MD

If you didn’t tune into #AHA21 “Novel Strategies to Promote Healthy Vascular Aging,” you missed an exciting area of health and wellness that many of us care about: how can we and our patients live longer with reduced cardiovascular disease burden? The AHA makes it “simple” with Life’s Simple 7 that includes 1) managing blood pressure, 2) controlling cholesterol, 3) reducing blood sugar, 4) getting active, 5) eating better, 6) losing weight, and 7) cessation of smoking¹. However, this session on novel strategies provides additional directions to our roadmap to healthier arteries:

Adding a polygenic risk score to our current assessment of cardiovascular risk offers significant improvement in predicting CV events². By capturing more patients using precision medicine as Dr. Brooke Wolford presented, we can initiate lifestyle modification and statins earlier and reduce the rising rates in cardiovascular related deaths.
When vascular smooth muscle cells are exposed to continuous damaging stressors (aging, diabetes, CKD), they become osteogenic-like cells that undergo apoptosis and osteogenic differentiation which leads to more mineralization and calcification of the vascular wall³. While statins can increase coronary calcification, they get rid of the lipid in the plaque which leads to less risk of rupture. The question that remains to be answered is what does the calcium score reflect with regard to other clinical outcomes?
Dr. Catherine Shanahan eloquently presented that inhibitors of DNA-damage used in cancer treatment are also key drivers in mitigating vascular calcification⁴. If these drugs can prove safe in the future, they could be promising in the anti-aging of arteries. For now, lifestyle modifications such as dietary phosphorous have been implicated in premature aging. Do you know what foods have high dietary phosphorus? Processed foods.
Do you know what a flexitarian diet is? Dr. Walter Willett presented the EAT-Lancet Commission’s challenge of feeding 9.8 billion people by 2050 with a healthy AND environmentally sustainable diet. His explanation of this planet friendly, flexitarian diet is quite simple: 1 serving of dairy + 1 (optional) serving of other animal source foods (fish, poultry, eggs, red meat) per day⁵. The base of the flexitarian diet consists of nuts, soy, beans, fruit, vegetables, whole grains, and plant oils.
The combination of aging and being sedentary promotes a reduction in nitric oxide and an increase in superoxides and oxidative stress. As a result, suppression of endothelial function propagates cardiovascular disease. Dr. Anthony Donato’s research found that habitual aerobic exercise in older men prevents the decline in endothelial dependent dilation⁶. Post-menopausal women, however, did not derive the same benefit from exercise unless they were on hormonal therapy⁷. In essence, habitual exercise and its modulation on endothelial senescence is most likely sex and hormone-dependent.

There were additional highlights during this session that included the ABCDE’s of primary prevention presented by Dr. Roger Blumenthal that form the backbone of health and longevity⁸.

References: