Journal of Cardiovascular Development and Disease Review The Aging Vasculature: Glucose Tolerance, Hypoglycemia and the Role of the Serum Response Factor Hazel Aberdeen 1, Kaela Battles 2, Ariana Taylor 2, Jeranae Garner-Donald 2, Ana Davis-Wilson 2, Bryan T. Rogers 2, Candice Cavalier 2 and Emmanuel D. Williams 2,* 1 Department of Biomedical Sciences, Baptist Health Sciences University, Memphis, TN 38103, USA; [email protected] or [email protected] 2 Department of Biology and Chemistry, Southern University and A&M College, Baton Rouge, LA 70813, USA; [email protected] (K.B.); [email protected] (A.T.); [email protected] (J.G.-D.); [email protected] (A.D.-W.); [email protected] (B.T.R.); [email protected] (C.C.) * Correspondence: [email protected] Abstract: The fastest growing demographic in the U.S. at the present time is those aged 65 years and older. Accompanying advancing age are a myriad of physiological changes in which reserve capacity is diminished and homeostatic control attenuates. One facet of homeostatic control lost with advancing age is glucose tolerance. Nowhere is this more accentuated than in the high proportion of older Americans who are diabetic. Coupled with advancing age, diabetes predisposes affected subjects to the onset and progression of cardiovascular disease (CVD). In the treatment of type 2 diabetes, hypoglycemic episodes are a frequent clinical manifestation, which often result in more severe pathological outcomes compared to those observed in cases of insulin resistance, including premature appearance of biomarkers of senescence. Unfortunately, molecular mechanisms of hy- poglycemia remain unclear and the subject of much debate. In this review, the molecular basis of Citation: Aberdeen, H.; Battles, K.; the aging vasculature (endothelium) and how glycemic flux drives the appearance of cardiovascular Taylor, A.; Garner-Donald, J.; lesions and injury are discussed. Further, we review the potential role of the serum response factor Davis-Wilson, A.; Rogers, B.T.; (SRF) in driving glycemic flux-related cellular signaling through its association with various proteins. Cavalier, C.; Williams, E.D. The Aging Vasculature: Glucose Keywords: aging; serum response factor; vascular; glucose; hypoglycemia; heart Tolerance, Hypoglycemia and the Role of the Serum Response Factor. J. Cardiovasc. Dev. Dis. 2021, 8, 58. https://doi.org/10.3390/jcdd8050058 1. Introduction The exponential expansion of the older adult demographic (65 and older) in the United Received: 8 January 2021 States is unique in the nation’s history. By the midpoint of the twenty-first century, it is Accepted: 23 March 2021 estimated that Americans aged 65 or older will number approximately 90 million people, Published: 17 May 2021 and the number of older Americans just merely a decade into the twenty-first century will nearly double [1]. Publisher’s Note: MDPI stays neutral The rapid aging of the United States population is influenced by two primary factors: with regard to jurisdictional claims in published maps and institutional affil- (1) Americans are living longer than in previous decades and (2) there are more older iations. adults aged 65 and older than in previous generations, post-World War II. Americans are now living beyond their 70s, with many achieving centenarian status. The oldest of the “baby boomers” reached age 65 in 2011, setting off a phenomenon in the United States not previously observed. Since the start of 2011, and every day for the next 15 to 20 years, approximately 8000–10,000 Americans will observe their 65th birthday. In Copyright: © 2021 by the authors. the year 2030, when the last baby boomer turns 65, the demographic makeup of our Licensee MDPI, Basel, Switzerland. country will have changed greatly. Moreover, it is estimated that twenty percent of all This article is an open access article distributed under the terms and Americans—approximately 77 million people—will be aged 65 years or older [2]. conditions of the Creative Commons The aging demographic has had a widespread impact on essentially every component Attribution (CC BY) license (https:// of American society. At each transition from one life stage to the next in the lifespan of creativecommons.org/licenses/by/ those born after World War II, the United States has been impacted by their increased 4.0/). numbers and needs—from robust demand in commercial adolescent products as they J. Cardiovasc. Dev. Dis. 2021, 8, 58. https://doi.org/10.3390/jcdd8050058 https://www.mdpi.com/journal/jcdd J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 2 of 21 The aging demographic has had a widespread impact on essentially every compo- nent of American society. At each transition from one life stage to the next in the lifespan of those born after World War II, the United States has been impacted by their increased J. Cardiovasc. Dev. Dis. 2021, 8, 58 2 of 20 numbers and needs—from robust demand in commercial adolescent products as they entered into their teen years during the late 1940s and 1950s, to the infrastructural im- pacts via construction of thousands of new schools during the following decades, to the housingentered intoboom their of teenthe 1970s. years duringModern the times late 1940sdemon andstrate 1950s, that to the the baby infrastructural boomer’s popula- impacts tionvia constructioncontinues to ofexercise thousands its influence. of new schools Unquestionably, during the this following occurrence decades, will to have the housingits most significantboom of the impact 1970s. 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Thisincluding nearly polio 30 year and gain typhoid, in life expectancycease to be withinthe “doom a hundred-year and gloom” span di- agnosishad never that been they observed. once were Many at the of theturn pathologies of the century. that claimed While these our inhabitants “threats of of old” previous rou- tinelygenerations, present including significant polio health and challenges typhoid, cease in the to beUnited the “doom States, and these gloom” manifestations diagnosis thatare nothey longer once the were morbidity at the turn and of mortality the century. threat While in adults these“threats they once of old”were. routinely However, present other significant health challenges in the United States, these manifestations are no longer the pathologies have continued to be staples in the leading causes of death among Ameri- morbidity and mortality threat in adults they once were. However, other pathologies have cans. Since 1909, heart disease has been the leading cause of death among American continued to be staples in the leading causes of death among Americans. Since 1909, heart adults every year except in the period 1918–1920, when the Spanish Flu epidemic oc- disease has been the leading cause of death among American adults every year except in curred [4]. Moreover, since 1935, cancer has been the next leading cause of mortality in the period 1918–1920, when the Spanish Flu epidemic occurred [4]. Moreover, since 1935, Americans [5]. cancer has been the next leading cause of mortality in Americans [5]. According to the 2018 Centers for Disease Control & Prevention, both cancer and According to the 2018 Centers for Disease Control & Prevention, both cancer and heart heart disease risks are increased with advancing age (Figure 1; [6]). disease risks are increased with advancing age (Figure1;[6]). Figure 1. The 2018 Center for Disease Control and Prevention report on the leading causes of death from 2017 to 2018. 1 Figure 1. The 2018 Center for Disease Control and Prevention report on the leading causes of death from 2017 to 2018. 1 Statistically significant decrease in age-adjusted death rate from 2017 to 2018 (p < 0.05).2 Statistically significant increase Statistically significant decrease in age-adjusted death rate from 2017 to 2018 (p < 0.05).2 Statistically significant increase in in age-adjusted death rate from 2017 to 2018 (p < 0.05).NOTES: A total of 2,839,205 resident deaths were registered in the age-adjusted death rate from 2017 to 2018 (p < 0.05).NOTES: A total of 2,839,205 resident deaths were registered in the United States in 2018. The The 10 10 leading leading causes of death accounted for 73.8% of all deaths in the United States in 2018. Causes Causes of death are ranked according to number of deaths. Rankings for 2018 were the same as in 2017. Data table for Figure2 includes the number of deaths for leading causes. J. Cardiovasc. Dev. Dis. 2021, 8, 58 3 of 20 J. Cardiovasc. Dev. Dis. 2021, 8, x FOR PEER REVIEW 4 of 21 Figure 2.