Blogged Health

A couple of papers to compare and contrast:

Melatonin in relation to the "strong" and "weak" versions of the free radical theory of aging:

While the data supporting a role for melatonin in forestalling aging and prolonging life span per se is not compelling, the findings related to melatonin's ability to reduce the severity of a variety of age-related diseases that have as their basis free radical damage is convincing.

Melatonin prevents age-related mitochondrial dysfunction in rat brain via cardiolipin protection

Melatonin has been shown to possess antioxidant properties and to reduce oxidant events in brain aging. .... We found [that a number of] mitochondrial parameters were significantly altered with aging, and that melatonin treatment completely prevented these age-related alterations. These effects appear to be due, at least in part, to melatonin's ability to preserve the content and structural integrity of cardiolipin molecules, which play a pivotal role in mitochondrial bioenergetics.

Which is interesting to say the least; I would have lumped melatonin in with all the other antioxidant supplements - just because a chemical happens to affect some aspects of your biochemistry doesn't mean that ingesting it is going to have any positive benefit.

I have to wonder at what complexity is hidden here: a mechanism completely prevents alterations in mitochondrial parameters, and yet doesn't do anything for life span? Compare that with antioxidant chemicals targeted directly to mitochondria, which lead to significant extensions of healthy life. Mitochondria are complex objects, and (a) the state of their membranes, (b) the working of their inner processing mechanisms, and (c) the effects they have on their cell are not linked in straightforward ways.

The rational actor looks at risks to life and health ahead and acts to minimize those risks. Since we all have limited time and resources, we have to prioritize: we make lists, in our heads if nowhere else, putting the most likely and terrible outcomes up at the top. Highly unlikely but terrible outcomes don't receive much attention: meteors, lightning strikes, that sort of thing. Likely but merely unpleasant events might just be suffered as a cost of getting on with life: catching the flu is an obnoxious happenstance, but not particularly threatening for most of us. There are more important things to worry about while buying insurance and otherwise taking care of essentials.

So you end up with a list involving fires, car accidents, sudden implosion of the company you work for, that sort of thing. In that, most of us are not being terribly rational, as aging isn't on the list. It is absolutely going to happen, and it leads to the most terrible personal consequence possible - death - via numerous other very nasty personal consequences. Alzheimer's, heart disease, cancer, and all the rest. We all have a 100% chance of aging as things stand, and it's the worst thing that will happen to most of us. So why isn't it up near the top of that priority list?

On that subject, thoughts from a bioethicist I seem to be linking to a lot of late. Replace "we" with "I" and "society" with "an individual" and it works just fine:

the following four issues are vital:

1. The certainty of the harm (e.g. 0.1% vs 70% chance)
2. The severity of the harm (e.g. broken leg vs death)
3. The likelihood of mitigating the harm (e.g. 0.1% vs 70%)
4. The cost of mitigating the harm ($1 billion vs $1 trillion)

...

Aging increases one’s risk of disease and death. So the empirical evidence clearly shows that aging scores very high on (1) and (2). These facts alone show that aging is a BIG problem.

How about issues (3) and (4)? People are most likely to (mistakenly) assume aging research scores low on both these fronts. That is, people are skeptical that we can actually modify the biological processes of aging. But there are countless experiments in a variety of organisms that show aging is not immutable. And so the goal of retarding human aging scores reasonably well on (3). And once you add considerations (1) and (2) into the mix, it becomes evident that the current neglect of aging research is unjustified.

People will also falsely assume that (4) will require vast amounts of money. But here one must put things in their proper context. A lot of money compared to what? What we spend on national defence? National defense spending in the U.S. has reached approximately $1,600 per capita, compared to $97 per capita for federal spending on biomedical research (source)

Which I think is a fair summary of where things stand - aging is terrible, but those who would act to materially support longevity science don't believe that progress is possible, or that progress is cost-effective. Meanwhile, individuals pledge significant time and money for food, entertainment, and geopolitical machinations. You might want to refresh your memory as to the Strategies for Engineered Negligible Senescence (SENS) cost breakdown: a billion dollars over ten years to develop the medical technologies capable of rejuvenating aged mice in the laboratory, each of the seven branches of SENS requiring something like $15 million per year over that time.

Effective research is cheap compared to almost everything else connected with aging: the loss of wealth, deteriorating health, loss of contributing members of society, the elderly care infrastructure, and more. It's a great pity that support and fundraising lags so far behind the potential of longevity science.

BOSTON (Reuters) - Some of the intense care given to the smallest premature infants may be a little too intense, suggest two studies published on Wednesday.

One showed that light treatment for jaundice may overwhelm the smallest infants while another questions the practice of giving insulin to premature newborns.

Dr. Brenda Morris of the University of Texas Medical School in Houston and colleagues found that babies weighing less than 2 pounds (1 kg) were slightly more likely to die if they were given early light therapy for rising levels of bilirubin, the compound that can turn the skin yellow but, more dangerously, can cause permanent brain damage.

When the liver is slow to clear bilirubin, which can be toxic if too much accumulates, high-intensity light is used to break down the compound from outside the body.

The study of 1,974 infants, published in the New England Journal of Medicine, found aggressively treating rising bilirubin levels reduces the rate of brain injury in the form of cerebral palsy, blindness, severe hearing loss and poor cognitive development.

Only 26 percent of light-treated babies had brain damage, compared 30 percent for babies whose treatment was delayed until the levels got a bit higher.

But in the smallest babies, weighing 1.1 to 1.65 pounds (501 to 750 grams), those treated aggressively were 13 percent more likely to die than those who got conservative care.

The increase was not statistically significant, meaning not enough babies died to know whether the pattern is more than a fluke. Nonetheless, Morris said doctors may want to pause before rushing into light therapy.

"Aggressive phototherapy may be preferred for infants with birth weights of 751 to 1000 grams (1.6 to 2.2 pounds), because we found significant neurodevelopmental benefits in this subgroup and no evidence that the therapy increased the rate of death or other outcomes at 18 to 22 months," they wrote.

Dr. Rosemary Higgins, a researcher with the Pregnancy and Perinatology Branch at the National Institutes of Health and co-author of the study, said because jaundice "is one of the many medical problems they're facing, you need to look at these babies on an individual basis" to decide what treatment would be best.

The last study of light therapy was done in the 1970s, before advances allowed much smaller babies to survive.

A second team found that early insulin therapy offers little clinical benefit in very-low-birth-weight infants, putting them at risk of dangerous hypoglycemia or low blood sugar.

Their trial of more than 300 babies showed that putting them on continuous insulin from birth raised the risk of death, with nearly 12 percent dying after four weeks, compared to 5.7 percent of infants not given insulin.

"Mortality at 28 days was higher in the early-insulin group than in the control group," Dr. Kathryn Beardsall of Britain's University of Cambridge and colleagues wrote.

Copyright © 2008 Reuters Limited.

NEW YORK (Reuters Health) - Young people with attention-deficit hyperactivity disorder (ADHD) may be particularly vulnerable to serious nicotine addiction if they start smoking, a new study suggests.

Past research has shown that kids with ADHD are more likely than their peers without the disorder to start smoking. These latest findings suggest that once they do take up the habit, they also tend to become more severely nicotine-dependent, researchers report in the Journal of Pediatrics.

"The nicotine dependence appears to be about twice as bad," said lead researcher Dr. Timothy E. Wilens of Massachusetts General Hospital in Boston.

The study, which included 166 15- to 25-year-olds with and without ADHD, found that those with the disorder scored significantly higher on a questionnaire that gauges physical dependence on nicotine.

Their average score was double that of smokers without ADHD.

ADHD was not the only factor that influenced nicotine dependence, however. Young people who had a parent who smoked, friends who smoked or who lived with a smoker all tended to have more-severe nicotine addiction.

Importantly, Wilens told Reuters Health, these environmental factors all had a greater impact on study participants with ADHD. This suggests that a mix of biology and environment is at work, according to Wilens.

It's not clear why ADHD and smoking are linked, he explained, but there is evidence that nicotine affects brain systems believed to be involved in ADHD. One study, for example, found that nicotine and the ADHD drug Ritalin each had similar effects on a protein that regulates levels of the brain chemical dopamine.

Some recent studies have also suggested that nicotine can help alleviate ADHD symptoms.

It's possible, Wilens said, that some young people with ADHD are using cigarettes as a way to self-medicate.

The bottom line for parents of children with ADHD, he noted, is that they should discuss the importance of not smoking with their children, and make sure that their ADHD symptoms are minimized to the extent possible.

Parents should also be aware of the environmental factors that push some kids to smoke, Wilens pointed out. "If parents smoke, themselves," he said, "they should certainly stop."

SOURCE: Journal of Pediatrics, September 2008.

Copyright © 2008 Reuters Limited.

Mainstream research on the biochemistry of aging and longevity - with an eye to slowing down aging rather than repairing it - is at this time primarily focused on a small number of areas. One is the cluster of mechanisms and signaling pathways associated with insulin and insulin-like growth factor 1 (IGF-1). You might recall that a tenfold increase in nematode life span was engineered via manipulation of IGF-1, for example:

Reis' team discovered that a mutant in the insulin/ IGF-1 pathway of C. elegans slows development but ultimately produces adults he described as "super survivors," able to resist levels of toxic chemicals that would kill an ordinary worm. Although the adult lifespan of C. elegans is normally only two to three weeks, half of the mutant worms were still alive after six months, with some surviving to nine months.

While perusing PubMed, I noticed a couple of papers on insulin, IGF-1, and aging:

Insulin and aging

In invertebrates, signaling pathways homologous to mammalian insulin and insulin-like growth factor (IGF-1) signal transduction have a major role in the control of longevity. There are numerous indications that these pathways also influence aging in mammals, but separating the role of insulin from the effects of IGF-1 and growth hormone (GH) is difficult.

In mice, selective disruption of the insulin receptor in the adipose tissue extends longevity. Increases in lifespan were also reported in mice with deletion of insulin receptor substrate 1 (IRS1) in whole body or IRS2 only in the brain. GH deficiency or resistance in mutant mice leads to hypoinsulinemia and enhanced insulin sensitivity along with remarkably extended longevity.

These characteristics resemble animals subjected to calorie restriction. Studies of physiological characteristics and polymorphisms of insulin-related genes in exceptionally long-lived people suggest a role of insulin signaling in the control of human aging.

Role of the GH/IGF-1 axis in lifespan and healthspan: Lessons from animal models

Consistently, two interventions, caloric restriction and repression of the growth hormone (GH)/insulin-like growth factor-1/insulin axis, have been shown to increase lifespan in both invertebrates and vertebrate animal model systems. Caloric restriction (CR) is a nutrition intervention that robustly extends lifespan whether it is started early or later in life. Likewise, genes involved in the GH/IGF-1 signaling pathways can lengthen lifespan in vertebrates and invertebrates, implying evolutionary conservation of the molecular mechanisms.

Specifically, insulin and insulin-like growth factor-1 (IGF-1)-like signaling and its downstream intracellular signaling molecules have been shown to be associated with lifespan in fruit flies and nematodes. More recently, mammalian models with reduced growth hormone (GH) and/or IGF-1 signaling have also been shown to have extended lifespans as compared to control siblings. Importantly, this research has also shown that these genetic alterations can keep the animals healthy and disease-free for longer periods and can alleviate specific age-related pathologies similar to what is observed for CR individuals. Thus, these mutations may not only extend lifespan but may also improve healthspan, the general health and quality of life of an organism as it ages.

With the level of interest presently devoted to this subject, I imagine that a decade from now researchers will fully understand how IGF-1, insulin, growth hormone, and calorie restriction all fit together into the bigger picture of the natural range of metabolic processes in response to circumstances. Your diet and exercise choices change the way your biochemistry operates: the biochemical mechanisms by which this happens have a deep evolutionary history.

It seems evident that some large portion of the research community will continue to forge ahead with strategies to shift your metabolism into a better state for your long term health - replicating calorie restriction, or mutations known to be beneficial. This is not a path to radical extension of the healthy human life span, however. It will only produce modest gains. To move beyond the small goals, we have to aim to repair the damage of aging rather than just slow down its accumulation. It will be no harder to achieve from where we are now, and the rewards are far greater.