Moderation: M. Gogol, Coppenbrügge; A. Simm, Halle (Saale)
The progress in basic and clinical research leads to a growing knowledge about how to delay or to intervene if age associated decline occur. The primary goal therefore is not to extend lifespan but to extend healthspan. This new approach may foster the translational process from basic research to clinical action and include the interaction between aging processes and disease as well as vice versa. One major driver of aging are cardiovascular diseases and risk factors may act for years before suclinical, e.g. hypertension, or clinical diseases occur, e.g. heart failure. The aging heart seems often to be more a driver than a bystander for disease manifestations. Effective strategies to reduce risk factors and to strengthen primary and secondary prevention held the promise of extanding healthspan of the cardiovascular system. One of this concepts is the development of polypills – first published 2003 in BMJ – which contain various low-dose drugs like aspirin, ß-blockers, angiotensinogen receptor antagonist, statins, and others. As epidemiological data show potential benefits on a societal level, interventional studies showed mixed results up to now. One cause may be to identify the best combination of drugs as well as the optimal form of application, e.g. as all statins works well at coronary arteries it isn´t so in the brain. This symposium focus on bringing together researcher and clinicians with an interest in bench-to-bedside and bedside-to-bench research.
The elderly are often afflicted by multiple comorbidities and aging is itself the major risk factor for most of these chronic diseases and disabilities. Definition of the major pillars that drive the aging process has allowed the emergence of interventions that target those pillars and in doing so, extend both lifespan and healthspan (the period of life spent in good health) in multiple animal models. Lifespan extension is often accompanied by a delay in the appearance and progression of not one, but most diseases of aging simultaneously, as well as a slowing in age-related functional decline. Geroscience represents a new approach to understand how basic biology of aging drives the risk for chronic diseases. As such, it represents a preventive approach that could affect how we address current and emerging clinical challenges of aging, by addressing the core major risk factor (aging), rather than individual diseases one at a time.
Cardiovascular diseases (CVD) remain the leading cause of mortality in developed nations, and aging is the main risk factor for CVD. Arterial dysfunction (large elastic artery stiffening and endothelial dysfunction) is a key mediator of increased CVD risk with aging. Oxidative stress, inflammation, reduced nitric oxide (NO) bioavailability and changes to the extracellular-matrix (ECM) of the arterial wall (increased collagen, reduced elastin, increased advanced glycation end-products) are the primary mechanisms of arterial dysfunction with aging. Thus, interventions that prevent or reverse arterial dysfunction with aging by modifying these mechanisms should reduce CVD risk in older adults. We have used “forward” and “reverse” translational approaches in cells, mice and people to establish evidence-based interventions to ameliorate arterial aging. Healthy lifestyle practices, including regular aerobic exercise, lifelong and short-term calorie restriction and reduced dietary sodium intake all improve, reverse or prevent arterial stiffening and endothelial dysfunction with aging as a result of lowering arterial oxidative stress and inflammation, increasing NO bioavailability and improving ECM changes in the arterial wall. Aerobic exercise also exerts a direct protective effect on aging arteries, shielding them from a variety of adverse influences, including elevated LDL-cholesterol and fasting blood glucose, and consumption of a Western (high fat, high sucrose) diet, in part by improving mitochondrial function/health. Several healthy lifestyle “mimicking” pharmacological/nutraceutical strategies also improve arterial function with aging via these mechanisms, including supplementation with curcumin, MitoQ (mitochondrial antioxidant), sodium nitrite (NO-boosting), autophagy enhancers (spermidine, trehalose) and activators of energy-sensing (e.g., sirtuin) pathways (nicotinamide mononucleotide and nicotinamide riboside). Mimicking the benefits of healthy lifestyle practices with novel behavioral interventions such as intermittent fasting (e.g., time-restricted feeding) also may preserve arterial function with aging. Overall, lifestyle- and pharmacologically-based strategies that maintain arterial function with aging hold promise for reducing age-associated CVD.
Cardiovascular disease in the elderly is most often going along with chronic low-grade systemic inflammation: Pathophysiology of both vascular and myocardial ageing as well as clinically overt cardiovascular disease is essentially linked to the modular stress response elements giving rise to a natural immune response.
An enhanced inflammatory state – i.e. “inflammatory/pathogen burden” – in the elderly on the one hand results from physiological immunosenescence and on the other hand is modified by the individual immune history: the latter is determined by sequential infectious/pathogenic events (“multiple hits”). Immunosenescence may prompt ageing of organs. Cardiac ageing can be assessed by analysing heart rate variability. Our hypothesis that the increasing “inflammatory/pathogen burden” of each organism during a lifetime significantly contributes to the cardiac ageing process is grounded on the fact that a characteristic feature of the ageing heart – a narrowed heart rate variability – can be experimentally induced in humans and mice by an inflammatory stimulus (endotoxin). Physiological organ aging processes and immunosenescence provide possible explanations for the frequently atypical clinical presentation of severe ailments and altered pharmacokinetics in old age. Moreover, severe inflammatory hits (as seen in influenza) may provoke heart attack and stroke, so that infectious diseases can induce acute major cardiovascular events.
Chronic cardiovascular diseases are highly prevalent in geriatric patients. An individualized approach is mandatory in both prevention, diagnostic measures and therapy. Weighing benefits and risks, risk factor control and interventions may be helpful even for very old patients.
The combination of multiple low-dose blood pressuring drugs, aspirin, a statin, and folic acid in a polypill was first published in 2003 (Wald and Law, BMJ 326:1419). In clinical studies substantial risk factor reductions, safety, and improved drug adherence were demonstrated. The concept was extended from high- to low-risk individuals and showed efficacy and safety too but mainly in persons < 70 years and by the statin component more than the antihypertensive component. As cardiovascular diseases are a driver of aging and frailty the question is if and how the results can be translated to older individuals, where treatment goals and thresholds are different from younger ones, especially for lipid and antihypertensive lowering strategies, outweighing benefits and risks. Given the high diversity in the older population the polypill concept cannot denied in general but also not recommended to all older persons, e.g. for advanced frailty states. The presentation will discuss challenges and potential pitfalls for older people.