“I think we’re getting closer to harnessing neurogenesis to improve cognition and mood in humans. This research may also help explain a bit of a mystery in the field, which we still don’t understand, regarding how the hippocampus can be involved with both cognition – which is its classic function – and in mood and anxiety-related functions. Perhaps the fact that pattern separation affects both the cognitive and mood domains is the beginning of an answer to that paradox,” said Dr. Hen. _StemCells

René Hen, PhD, professor of Neuroscience and Pharmacology, in the Departments of Neuroscience and Psychiatry at Columbia University and the New York State Psychiatric Institute, has discovered a possible escape hatch by which some members of society might escape the Idiocracy. It involves the use of chemicals called “BAX inhibitors.” Particular members of that class of drugs have the potential to preserve newborn stem cells in the brain’s hippocampus. And doing that could make all the difference in the course of a person’s life success and happiness.

After boosting the number of neurons in the hippocampus, an area of the brain involved in memory and mood, the researchers tested the mice in both learning and mood-related tasks and looked for changes in behavior. The researchers found specific effects on learning tasks that involve a process called pattern separation, which is the ability to distinguish between similar places, events and experiences.

“This process is crucial for learning because it enables us to know whether something is familiar or novel,” said Dr. Hen. “If it is familiar, you move on to the next bit of information; if it’s novel, you want to be able to recognize that it’s new and give it meaning. These mice, with just more adult-born neurons, and no other changes in the brain, basically learn better in tasks where they have to discriminate between similar contexts.”

Earlier strategies for manipulating neurogenesis, according to the investigators, were broader and less specific. “In addition to stimulating neurogenesis, these earlier methods exerted many other effects on the brain. As a result, you never knew with these older manipulations what’s due to neurogenesis, or what’s due to the other effects that these manipulations cause, and, indeed, what we find is that when you stimulate just adult neurogenesis, you actually get a subtle effect. Unlike broader manipulations, it does not affect all forms of learning, it’s very specific to tasks that require pattern separation,” said Dr. Hen.

Pattern separation is not only important for learning; it may also be important for anxiety disorders, including post traumatic stress disorder (PTSD) and panic disorder. People with PTSD, say the researchers, have a more generalized fear response, so that when they are placed in a situation that reminds them of even one aspect of their trauma, they frequently have a full fear response.

…The researchers say that the genetic strategy used to stimulate neurogenesis in their experiments can be mimicked pharmacologically, potentially leading to the development of new drugs to reverse pattern separation deficits. One such class of drugs the investigators are currently testing – BAX inhibitors – works by blocking cell death.

“These drugs are basically doing the same thing that we did with our genetic manipulation-namely, increasing the survival of the young neurons which normally undergo a process of cell death that eliminates at least half of these neurons. Now instead of dying, the neurons will go on to survive,” said Dr. Sahay.

Some BAX inhibitors have been developed for stroke research, where the goal has also been to prevent neurons from dying. The Columbia researchers plan to begin testing the BAX inhibitors in mice shortly. And if they produce cognitive benefits, the testing will be extended to clinical trials to determine if there’s also a beneficial effect in humans. _StemCells

This is all related to the length of time required before antidepressants are able to bring about a full “antidepressive response.” The full effect of modern antidepressants requires new stem cell production in the hippocampus — but that takes time to achieve. Drugs capable of rapid and prolonged increases of hippocampal stem cells could conceivably keep anxiety and depression at bay, while improving a person’s cognitive capacity.

No, this is not NZT. As mentioned here previously, a drug that could achieve the effect of the fictional NZT would have to stimulate changes in gene expression on multiple levels, and across a wide range of brain centers.

Smart drugs alone will not achieve the goal of smarter, better-rounded, and happier humans. Educational and environmental interventions would also be necessary, to blunt the Idiocratic brainwashing effect of modern media, modern academia, and modern popular culture, while allowing the brain to develop newer, more functional pathways.

Realistically, it will take 15 years at the earliest to see the early promise of this type of medication come to fulfillment. But a single ray of hope in the distance is worth a lot to a person immersed in the modern rush to Idiocracy.

More 5April2001: An example of rapid brain plasticity in human adults
The PNAS Abstract from the actual study

Previously published at Al Fin

As noted here before, improved neurogenesis in the hippocampus is associated with antidepressant and anti-anxiety behaviours in animal studies — and probably in humans. It does no good to live longer with younger brains if we are unable to enjoy our added time and brainpower.

Al Fin Longevity

Dror Sagi (Stanford; Kim lab) — Engineering a long-lived worm

If aging is an engineering problem, then we should be able to solve the engineering challenges more easily in simple systems.

By introducing genes regulation from a long-lived organism into the genome of a short-lived organism, it should be possible to add pro-longevity functions – in effect “upgrading” the short-lived animal so that it lives longer. Sagi has set out to do just that, by transferring genes from the long-lived zebrafish (4-year lifespan) to the short-lived work (4-week lifespan).

The first gene he described was the UCP2 gene, the subject of an earlier talk. Expressing fish UCP2 in the worm lowers overall ATP, and extends worm lifespan. As an important control, expressing an additional copy of the worm UCP2 under the same promoter control does not extend life.

Likewise, fish lysozyme results in lower daf-16 activity, and also extends lifespan. The fish enzyme appears to act by decreasing the pathogenesis from E. coli, an unnatural food source for the worm that causes health problems in late life.

Overall, Sagi characterized 5 well-characterized longevity pathways, testing 16 genes and getting 7 hits.

The next obvious question: Can “upgrade” genes be combined to further increase lifespan? Indeed they can: several pairwise combinations of genes combined to extend lifespan longer than either single gene alone. At some point it worked a little to well: the lifespan of the worms started getting long enough that the survival curves became unwieldy.

• Staying with the worm…

Monika Suchanek (UCSF; Kenyon lab) — The germline and somatic reproductive tissues influence C. elegans

Classically, it had been assumed that there is a tradeoff between lifespan and the number of progeny produced over the lifespan. We now know that this isn’t necessarily true; there are several examples of long-lived mutants that have a normal number of progeny (though the kinetics may be slower, which poses an issue with respect to fitness: if I live twice as long as you and have the same number of progeny but half as quickly, I will probably lose the evolutionary race).

Suchanek began by reviewing old data (like, from when I was a rotation student in the Kenyon lab: old) demonstrating that removal of the germ cells results in lifespan extension, but that this longevity enhancement requires the presence of the somatic gonad. This loss of the germline causes nuclear accumulation of the DAF-16/FOXO protein in the intestine. It is clear from several diverse pieces of data that the somatic gonad and germ line exert their effects on longevity somewhat independently.

Two other genes, daf-9 and daf-12 are required for the extended longevity of germline-deficient worms. DAF-9 is an enzyme that makes dafachronic acid, the ligand of a receptor encoded by DAF-12. Addition of dafachronic acid has no effect on lifespan of germ-cell-deficient, somatic-cell-competent cells, but it does extend the lifespan of animals that lack both germ cells and the somatic gonad.

How does the intestine know that the germ line is gone? To answer this question, Suchanek screened a “signaling sublibrary” of 1304 genes, and got 115 unique hits including several components of the Wnt pathway. Two components, mom-2 and wrm-1 (ß-catenin), are required for nuclear accumulation of DAF-16/FOXO and for the extended lifespan of germline-deficient worms. Suchanek favors a model in which germ line cells emit Wnt inhibitors.

• Finishing on a strong note…

Monique Stanfel (Buck Institute; Kennedy lab) — Ribosome Function and Aging

The Kennedy lab is interested in identifying longevity/aging genes that are conserved in yeast and worm, and then testing these in the mouse.

In both yeast and worm, deletion/knockdown of many ribosomal proteins (RPs) can extend lifespan. In yeast, most if not all of the RPs with a role in lifespan are components of the large subunit (60S). In worm, knockdowns of both small and large subunit components can increase lifespan. Three of the genes conserved between worm and yeast can be knocked down in mice.

In order to characterize translation in mouse mutants, Stanfel ran polysome gradients on liver tissue. She analyzed the fractions in two ways, looking at both ribosome-associated RNAs and at the ribosome-associated proteins.

Surprisingly, the Rpl22 gene can be knocked out and has very little effect on global translation in the mouse liver. This may be because a homologous gene, Rpl22L (“-like”) is compensating for the loss of the major species.

Knockout of another gene, Rpl29, has a larger effect on global translation, decreasing the levels of 80S ribosomes. When fed a high-fat diet, Rpl29 knockouts were protected against weight gain, and their blood glucose also remained low; furthermore, the animals were leaner than wildtype. They also resist developing cardiac hypertrophy in another assay – thus, they meet all the preliminary criteria for the time and resource investment of a lifespan study.

Research indicates that anxiety symptoms are more prevalent in elderly people than in any other age group, occurring at about twice the rate of younger adults. The types of anxiety disorders most common among the older population include generalized anxiety, mixed anxious-depressive syndrome symptoms, and phobias (often characterized by exaggerations of rational concerns). More rare are late-life onset of obsessive compulsive disorders (OCD) and panic disorders. (more…)

Over the past 60 years, many documents, including the 1948 Universal Declaration of Human Rights, have addressed the rights of all persons. But it was not until the Declaration on Social Progress and Development in 1969 that the human rights of the elderly were specifically mentioned in an international rights document (Office of the United Nations High Commissioner for Human Rights). The United Nations adopted the first International Plan of Action on Ageing in 1987 and the General Assembly of the United Nations adopted the Principles for Older Persons in 1991. (more…)

As mentioned earlier, the tendency to reminisce as we grow older was regarded by many gerontologists as a pathology until Robert Butler showed it could be a highly positive way of integrating experiences and coming to terms with the past. As such, life review became a method for group therapy, creative writing groups, and as a source for living history drama. Some researchers went even further. They described elements of wisdom and aging creativity in the life review process. Not only were older adults of learning and expressing themselves, but because of their treasure house of past experience, they could also be ideal students and could make excellent teachers. (more…)

It is in this same period that college-and university-based Institutes for Learning in Retirement (ILRs, later renamed Lifelong Learning Institutes, or LLIs) arose. The prototype for subsequent LLIs was the Institute for Retired Professionals established in 1962 at the New School for Social Research (now New School University) in New York City. Only a handful of the member-led, member-taught, educational programs had appeared by the mid-1970s but by the mid-1980s there was a sharp rise in the rate of new programs started each year, until, by 2000, there were more than 400 of these programs across the United States and Canada. (more…)

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In past decades, the traditional understanding of education, which was exclusively oriented toward formal learning in childhood and young adulthood, has been broadened to the concept of lifelong learning. Different versions of this concept have in common the idea that learning in different phases of human life span, (more…)

The term education describes the process of acquiring abilities, skills, experiences, and knowledge systems as well as the results of this process. Specific contents of education reflect general cultural values and preferences of social environments and milieus, social change, and societal progress. (more…)