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A Gene's eye view of health as buying time.

Recently researchers have identified an important genetic component to heart health, a result of their continued exploration of the role of LDL ("bad" cholesterol) in the body. The discovery is startling because of its specificity: the large genetic study published in November in NEJM has identified 15 rare mutations that block the activity of a specific gene, Niemann-Pick Cl-Like 1 (NPC1L1). People who carry one of these genetic mutations enjoy a significantly lower LDL level than non-carriers (the mean lowered amount in the study was 12 mg/dL).

The practical implications are even clearer: The carriers of the mutations had a 53% risk reduction specifically in coronary heart disease, as compared to non-carriers of a NPCILl-blocking mutation. This large of a reduction in heart disease risk was previously not known. NPC1L1 is the same gene that is blocked by the cholesterol-lowering drug ezetimibe. We now have a glimpse at the potential of the drug, due to the identification of the mutations.

Ezetimibe lowers plasma levels of LDL cholesterol by inhibiting the activity of NPC1L1. By studying human mutations that inactivate this gene and then looking at data on their health outcomes, we can now infer the specific potential effects of the drug.

There is one final, important point to be made about the role of the discoveries in heart health advisories going forward, and it is easy to overlook. The senior author of the study comments: "One of the key concepts here is that it may not be 'how you lower LDL' or 'how low you take LDL' but rather 'how long the LDL is lowered.' We should think about LDL like we do smoking. Smoking is typically quantified as 'pack-years,' a product of the number of years smoked times the number of packs per day. The concept to stress may be 'LDL-years.'"

The focus on this concept is not unlike the conclusions drawn from a lifetime of work by Steven N. Blair, P.E.D., with colleagues at the Cooper Aerobics Clinic in Dallas, and geriatrician Walter Bortz II, that have analyzed huge numbers of available statistics on aging and death and now assess potential longevity directly in terms of exercise years.

In 1989, Blair's seminal paper, "Physical Fitness and All-Cause Mortality," reported to the world the direct relationship between how long you will live and how fit you are. By analyzing data from over 13,000 people over more than a decade, he has determined what percentage, on average, each of several factors contributes to our mortality.

The prospective study Blair conducted examined physical fitness and risk of all-cause and cause-specific mortality in 10,224 men and 3,120 women who were given a preventive medical examination. Physical fitness was measured by a maximal treadmill exercise test. The study notes that average follow-up was slightly more than 8 years, for a total of 110,482 "person-years" of observation. There were 240 deaths in men and 43 deaths in women.

The authors report: "Age-adjusted all-cause mortality rates declined across physical fitness quintiles from 64.0 per 10,000 person-years in the least-fit men to 18.6 per 10,000 person-years in the most-fit men (slope, -4.5). Corresponding values for women were 39.5 per 10,000 person-years to 8.5 per 10,000 person-years (slope, -5.5). These trends remained after statistical adjustment for age, smoking habit, cholesterol level, systolic blood pressure, fasting blood glucose level, parental history of coronary heart disease, and follow-up interval."

Lower mortality rates in higher fitness categories were seen specifically for cardiovascular disease and cancer. Also, low fitness level was an important risk factor. The study concludes, "Higher levels of physical fitness appear to delay all-cause mortality primarily due to lowered rates of cardiovascular disease and cancer."

Human aging is plastic, contends Walter Bortz, after carefully looking at Blair's data and drawing a thoughtful and quite important distinction between aging and disuse, in 1982, seven years before Blair's published work in JAMA. The essential idea of that paper, called "Disuse and Aging," and also published in JAMA, is that what often passes for aging isn't aging, but disuse. Dr. Bortz is fond of saying that aging is not a disease; it isn't something to be treated. He points to the second law of thermodynamics. Aging is the effect of an energy flow on matter over time. It ultimately is entropy, heat loss. We as organisms capture energy, and how effectively we use oxygen is in Walter's view our central biomarker.

Finally, there is aging itself. In a paper entitled, "How Fast Do We Age?" Bortz plotted age-related decline across athletes aged 20 to 70. No matter their sport, the athletic records revealed the same statistical reality for all: Aging itself cost % of a percentage point per year in human wellness. Everything ages: cars, people, canyons. The exciting, empowering central idea is that the rate of loss is entirely knowable.

Bortz invites us to consider that once you've lost 70% of your fitness, symptoms begin--shortness of breath, musculoskeletal frailty, etc. This is the point of contact with the medical system for most people; they become patients, but with only 30% left in their health bank accounts. Ten percent later, they might well be dead.

He puts it succinctly: If at age 30 you have 100% of your health, at age 80 you would have necessarily lost only 25%--if you are fit. Blair's data shows, on the other hand, that if you are unfit, you lose 2% per year of your health. Your "health" in this context simply means what you've been naturally given to let you live as long as that % percent per year loss due to aging will allow. We falter, contends Bortz, by succumbing to inactivity.

NEJM, 2014, Vol. 371: pp. 2072-2082,

"The Plasticity of Human Aging," July 2012, Walter Bortz II, MD, Trinity College Dublin lecture,

JAMA, 1989, Vol. 262, No. 17, pp. 2395-2401
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Publication:Running & FitNews
Geographic Code:1USA
Date:Nov 1, 2014
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