The Aging Brain: Endangered by Runaway Development?

Mehmet Somel, a Turkish researcher doing post-doctoral work in Shanghai, has uncovered some fascinating genetic evidence suggesting that inappropriate-for-age gene regulation may be endangering aging brains:

Researchers have now identified a gene regulatory link between changes in the young and aging brain.

The brain undergoes rapid growth and development in the early years of life and then degenerates as we progress into old age, yet little is known about the biological processes that distinguish brain development and aging.

Underlying brain development is the complex and coordinated process of gene regulation.

"In development, many genes are turned on and off by regulators, such as transcription factors and microRNAs. The question is, do all of these regulatory processes cease once adulthood is reached, or are they still active in aging?" said Mehmet Somel, postdoctoral researcher at the Shanghai Institutes for Biological Sciences.

The researchers investigated messenger RNA (mRNA), microRNA, and protein expression changes in the prefrontal cortex of humans and rhesus macaque monkeys over the life span of each species.

The group found that distinct patterns of gene regulation in the prefrontal cortex do not stop at maturity, instead persisting into old age, a phenomenon that was observed for many different functional processes.

...The researchers showed that this process begins as early as three to four years of age, suggesting that these changes may be normal developmental regulation that continues long into old age.

While this regulation is likely to be beneficial during development, at old age continuation of the gene regulation, or "runaway" development, might be detrimental.

Interestingly, they found the runaway neuronal development to be conserved in macaques, but it occurs an accelerated rate.

Because the regulatory processes progress much faster, the authors suggest that this could be a significant contributor toward limiting the life span of macaques to only about one-third that of humans. _SiFy

Researchers will now need to determine whether a more "age-appropriate" pattern of gene regulation would allow for persistence of normal brain functioning further into old age.

It is known that DNA repair loses efficiency with increasing age. If inappropriate genes are consistently "over-clocked" at levels more appropriate to younger ages, the compounding of genetic errors due to inefficient DNA repair would occur more quickly and take on more significance.

This is a fascinating area of study, well worth following.

Can Delaying Puberty & Extending Childhood Increase Lifespan?

Puberty seems to be arriving at earlier ages for both boys and girls. There are many reasons why puberty onset is earlier now, but most of these reasons are still unclear. The problems that arise from premature puberty include violence, higher risks of cancer and diabetes, increased behavioural problems (drugs, alcohol, delinquency etc), isolation from peer groups -- even a change in growth rates for the children of girls with premature onset of puberty.

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...children who go into early puberty are prematurely sexualised and too immature to deal with the implications. They are more vulnerable to sexual abuse, inappropriate sexual behaviour, sexually transmitted diseases and teenage pregnancy. “It means that children develop sexually much earlier,” Stanhope says. “They are physically ready for sexual reproduction but mentally completely unready.”

Studies have shown that adolescents who go through puberty earlier are involved in more risk-taking behaviour, such as taking drugs, binge drinking and breaking the law. A premature increase in testosterone can lead to aggression in boys who lack the maturity to control impulses. “We all realise that testosterone is a very difficult hormone to learn to live with,” Stanhope says, tapping a pencil vigorously on his pockmarked table, “and if you get a rise in testosterone outside the normal physiological age, then it’s even more of a problem.”

Research published this year in the Australian and New Zealand Journal of Criminology also found increased aggression in girls who reached puberty early. In Britain the uncomfortable reality that children are becoming sexually mature earlier has been overlooked in the recent debate about the over-sexualisation of children. Instead of simply focusing on cynical manufacturers producing padded bras for seven-year-olds, perhaps we should also consider how to respond to the new reality that some girls are now growing breasts at this age.

Stanhope also points out that for women there may be long-term health problems, because early puberty increases exposure to oestrogen. According to Cancer Research UK, a girl who has her first period a year later than her contemporaries has 5% less risk of developing breast cancer in later life. “There may be an important link with breast and ovarian cancer,” Stanhope says. “The earlier a girl has her period, the longer her exposure to oestrogen and this may well have very important sequelae for oestrogen-dependent tumours. This increases her risk of breast cancer, ovarian cancer and of developing cardiovascular problems.”

Girls who reach puberty early are also more likely to develop type 2 diabetes. A 37-year-long study of 61,000 Norwegian women showed that women who got their first period at ten or 11 had a 10% higher mortality rate than those who got their period four years later. _PubertyBlues

Scientists are beginning to home in on the physiological initiators of puberty, and have found a way to delay puberty in mice. By "knocking out" a specific gene, IGF-1R, researchers have both delayed puberty and maintained normal reproductive function after puberty in these knockout mice.

Pubertal onset, initiated by pulsatile gonadotropin-releasing hormone (GnRH), only occurs in a favorable, anabolic hormonal milieu. Anabolic factors that may signal nutritional status to the hypothalamus include the growth factors insulin and IGF-1. It is unclear which hypothalamic neuronal subpopulation these factors affect to ultimately regulate GnRH neuron function in puberty and reproduction. We examined the direct role of the GnRH neuron in growth factor regulation of reproduction using the Cre/lox system. Mice with the IR or IGF-1R deleted specifically in GnRH neurons were generated. Male and female mice with the IR deleted in GnRH neurons displayed normal pubertal timing and fertility, but male and female mice with the IGF-1R deleted in GnRH neurons experienced delayed pubertal development with normal fertility. With IGF-1 administration, puberty was advanced in control females, but not in females with the IGF-1R deleted in GnRH neurons, in control males, or in knockout males. These mice exhibited developmental differences in GnRH neuronal morphology but normal number and distribution of neurons. These studies define the role of IGF-1R signaling in the coordination of somatic development with reproductive maturation and provide insight into the mechanisms regulating pubertal timing in anabolic states. _JCI

Scientists will find additional triggers for pubertal onset besides insulin and IGF-1, and some of those factors may provide a more benign approach to the delaying of puberty.

Paradoxically, IGF-1 is vital for normal development of mice, but knocking out IGF-1 receptors in certain flies and worms can increase lifespan. That paradox is still being studied.

So -- how long should puberty be delayed, if at all? If childhood could be extended for several more years without impairing the ability of the child to learn and mature psychologically, would the potential health and societal benefits be worth the postponement of sexual development of the child?

What if aging itself were to be postponed along with puberty? If total lifespan were extended by the number of extra years a person spent in childhood, would that be beneficial to society or not? What if a person could live an extra 20, 30, or 50 years -- but had to spend those extra years as a pre-pubertal child. Would it be worth it?

Those who see increased longevity as a sure path to overpopulation collapse of Earth's ecosystem, would insist upon some form of sterilisation for those who opt for longevity. In some countries, laws of that type -- mandating permanent sterilisation for anyone undergoing longevity treatments -- should be expected.

Extended pre-puberty is a form of time-limited and (probably) reversible sterilisation, so any longevity approach that also delayed puberty significantly, should not raise the hackles of those suffering from overpopulation anxiety too much. But there are likely to be a large number of objections to such treatments, all the same.

Modern societies appear to see children in a schizoid manner. Fewer children are born, so the one or two children a family does have, are cherished and pampered. On the other hand, children are seen as a hindrance to a hedonic lifestyle, an exorbitant expense and often a great bother. Overall, most children do not seem to be raised or educated very well in modern societies, judging by observable results.

While childhood is not prolonged in modern societies, an incompetent adolescence is certainly prolonged -- in many cases indefinitely. Given the choice between a prolonged childhood leading into an accelerated but prepared-for adolescence, and the current state of lifelong incompetent adolescence commonly seen in the affluent world, most Al Fin mental health professionals would choose the prolonged childhood combined with a prepared-for adolescence that leads into a responsible and competent adulthood.

Previously published at Al Fin

A New Class of Molecules that May Cure Alzheimer's

New nerve cells are constantly born in the hippocampus, but even in the normal adult brain, most of these newborn neurons die before they become functional.

And they fare much worse in the hippocampus of Alzheimer's patients.

Physical activity, an active social life and other intellectually and emotionally enriching experiences promote the birth and maturation of new neurons.

The scientists wanted to find compounds that can protect newborn neurons from dying.

P7C3 was selected from among about 1,000 compounds tested on mice.

The compound was found to help the survival of neurons in adult mice, which were genetically engineered to lack a gene that is crucial for the survival of newborn nerve cells. _IndiaToday

ScienceDaily
University of Texas Southwestern have reported in Cell the discovery of a molecule -- P7C3 -- that has the ability to protect brain cells, and trigger the production of new neurons. The scientists believe that new compounds in the same class as P7C3 may hold the key to slowing or temporarily reversing the progress of Alzheimer's Disease and other neurodegenerative conditions.

In a new study published today in the journal Cell, researchers screened 1000 molecules in mice to see which ones enhanced production of new neurons in a brain area involved in learning and memory. This region, known as the hippocampus, is one of two spots known to birth new neurons in the adult mammalian brain. It takes 2 to 4 weeks for the cells to migrate to the appropriate location and integrate into the existing neural circuitry, and many of them die along the way.

The researchers found that one compound, dubbed P7C3, protected these newborn neurons from dying. When given to mice genetically engineered to have very little new nerve cell growth, the compound seemed to repair the abnormal hippocampus. It could also increase birth and survival of new neurons in older rats, according to a press release from UT Southwestern Medical Center. The animals also had improved memory: they could better remember the location of a platform submerged in water, a standard test of learning and memory in rodents.

...

According to a release from the journal Cell, where the paper was published;

Two other drugs (Dimebon and Serono compounds) - both of which bear structural similarities to P7C3 -also encourage the growth of new neurons. It's tempting to think that all three compounds work in the same way.

In fact, Dimebon first came to the attention of researchers based on anecdotal reports by Russian physicians that the drug may ameliorate the symptoms of age-related cognitive decline. Unfortunately, unpublished reports from a phase 3 clinical trial have since failed to provide evidence that the drug could stave off the memory loss that comes with Alzheimer's disease.

In light of the new findings, it may be worth another look. "The speculative idea that these chemicals share a common mode of action will only be rigorously tested upon identification of their molecular target(s)."

 _TechnologyReview

Pieper, McKnight and colleagues tested more than 1000 small molecules in living mice. One of the compounds, designated P7C3, corrected deficits in the brains of adult mice engineered to lack a gene required for the survival of newborn neurons in the hippocampus. Giving P7C3 to the mice reduced programmed death of newborn cells -- normalizing stunted growth of branch-like neuronal extensions and thickening an abnormally thin layer of cells by 40 percent. Among clues to the mechanism by which P7C3 works, the researchers discovered that it protects the integrity of machinery for maintaining a cell's energy level.
To find out if P7C3 could similarly stem aging-associated neuronal death and cognitive decline, the researchers gave the compound to aged rats. Rodents treated with P7C3 for two months significantly outperformed their placebo-treated peers on a water maze task, a standard assay of hippocampus-dependent learning. This was traced to a threefold higher-than-normal level of newborn neurons in the dentate gyrus of the treated animals. Rats were used instead of mice for this phase of the study because the genetically engineered mice could not swim.
Prolonged treatment of aged rats with P7C3 also enhanced the birth of new neurons. "Aged rats normally show a decline in neurogenesis associated with an inability to form new memories and learn tasks," Pieper explained.

In their study, rats treated with P7C3 each day showed evidence of an increase in the formation of newborn neurons and significant improvements in their ability to swim to the location of a missing platform, a standardized test of learning and memory in rats.

The researchers pinpointed a derivative of P7C3, called A20, which is even more protective than the parent compound. They also produced evidence suggesting that two other neuroprotective compounds eyed as possible Alzheimer's cures may work through the same mechanism as P7C3. The A20 derivative proved 300 times more potent than one of these compounds currently in clinical trials for Alzheimer's disease. This suggested that even more potent neuroprotective agents could potentially be discovered using the same methods. Following up on these leads, the researchers are now searching for the molecular target of P7C3 -- key to discovering the underlying neuroprotective mechanism. _ScienceDaily

The study was two-tiered: First the scientists screened over a thousand small molecules in knockout mice, to find the one that provided the best protection for new hippocampal neurons. Then they tested the compound in senescent rats, looking for both behavioural improvements and better survival of new hippocampal neurons. They were successful on all counts.

H/T Brian Wang of NextBigFuture

Cross-posted to Al Fin