Strategies for Engineering Negligible Senescence – Report from SENS-6

Aubrey de Grey has rallied the world’s scientific community and its funders to attack the biological basis of aging, which underlies the majority of disease and suffering in the developed world. Since 2003, he has organized bi-annual conferences, bringing together innovative biologists, medical researchers and a few policy wonks to share knowledge and perspectives, to coordinate and support each others’ efforts. Below I report highlights from this year’s meeting, SENS 6, which I attended last week at Queens College, Cambridge.

 

Caloric Restriction in Monkeys – Reconciling Two Studies

This year and last year, two parallel studies of caloric restriction in rhesus monkeys reported their results. Science reporters framed their conclusions as contradictory. In Madison, the CR monkeys lived longer, while in Baltimore, they did not. Both studies reported robust benefits for many aspects of health in the CR monkeys. What I learned last week was that the Baltimore monkeys had a much leaner diet than the Madison monkeys. In fact, the control monkeys in Baltimore – those that were supposed to be “fully-fed” – got about as many calories per day as the CR monkeys in Madison. A natural interpretation of the two results is that modest CR extends life span but that severe CR doesn’t extend life span further (though it may improve health and lower rates of cancer and heart disease).  Read more

Another interesting subplot: the Madison diet formula was both high-fat and high-glycemic index, while lower in protein than the Baltimore formula. The Madison diet was completely synthetic (so it could be precisely controlled) including 28% sucrose. The Baltimore diet was based on whole grains and fish meal, with the rationale that there are micronutrients in whole foods that may be important though we have not yet catalogued them. When two groups of mice were fed on these two formulas, adjusted to the same number of calories, the ones on the Madison diet gained weight while those on the Baltimore diet did not. This echoes a theme that is reported in Scientific American this month: the body’s caloric budget is not the primary determinant of obesity. The same number of calories from different sources can have dramatically different effects on metabolism. I’ll write more on this next week.

 

Exercise vs Caloric Restriction

For the last ten yeas, Luigi Fontana of Washington University St Louis has been conducting an ongoing study of two groups of people who exercise fanatically (by middle-class US standards) and who seriously restrict their food intake (same standard). Both groups have dramatically improved biomarkers compared to the average American couch potato. There are some differences between the two. Exercise seems to be better for lowering markers of insulin resistance – the “metabolic syndrome” or “Type 2 Diabetes” that underlies the diseases of old age. Diet works better to lower cardiovascular risk factors. Both work to lower indicators of cancer risk.  (It will be many years before there is data to evaluate the effect of CR on human mortality.)   Read more

 

An aging clock in the brain

Dongsheng Cai of Einstein Medical Center in New York reported that age-related inflammation is especially prominent in a region of the brain called the hypothalamus, which is known to regulate body rhythms. The hypothalamus is especially sensitive to a signal hormone called NFkB that has damaging effects over the whole body. In experiments with flies and mice, life span can be extended by blocking the action of NFkB. Read more

 

Spermidine

Frank Madeo of University of Graz in Austria reported on experiments with a small molecule called spermidine. Fed to yeast cells, it increases life span dramatically, with smaller but still significant effects in flies and worms. Life span of mice can be increased by about 10% with spermidine in the diet. The mechanism seems to be stimulation of the process called autophagy, by which each cell cleans up its waste products, digesting them in organelles called lysosomes. Spermidine is part of the body’s metabolism, but its concentration declines with age. It is not available as a supplement, to my knowledge. The best dietary source is a Japanese fermented soy product called natto, which is famous for its vile flavor. Other dietary sources include soy products and wheat germ. And yes, it is found at high concentrations in semen.   Read more

 

Alternative to Chemotherapy and Radiation

Dr M Rigdon Lentz (an American) runs a German clinic with a unique cancer treatment. Cancer cells protect themselves from attack by the body’s immune system by spitting out many “false target” molecules that attract killer T cells in the blood and distract them from the real culprit, the cancer cells themselves. Lentz’s procedure involves filtering these decoy molecules from the blood. Often this is sufficient to initiate a fierce immune assault on the tumors, which flare up hot and red. Lentz described some dramatic cures. He reports major regression of tumors in 70% of his patients, despite the fact that most of them have been treated previously with chemo and/or radiation and traditional oncology has given up on them.    Read more

 

DRACO – kills all virus-infected cells

Todd Rider of MIT is quietly witty on-stage and charmingly self-effacing, but his program is radically ambitious. He wants to cure all infectious disease.

DRACO is an acronym for Double-stranded RNA-Activated Caspase Oligomizer. Start with the observation that single strands of RNA are used in all cells, but double-stranded RNA is found only in cells infected by viruses. The DrACO molecule has three parts: One part speaks to the body’s “mail system” that looks at address tags on a molecule, and uses those to send them to a particular cell. DRACO molecules are targeted to a particular kind of cell that is infected. Part two is a detector of double-stranded RNA. And if dsRNA is found, then part three is activated: molecular signals that trigger cell death. The bottom line is that DRACO molecules can find cells that are infected with any virus, distinguish them from uninfected cells, and selectively signal the cell to destroy itself. It’s been tested in test tubes and in mice it cures, for example, the flu. Rider’s lab is producing only tiny quantities of DRACO at present, but by year’s end he hopes to ramp up production for much wider testing.   Read more

 

RTEs = Retro Transposable Elements

Half of our DNA consists of repetitious stretches of DNA that never get translated into proteins. This was once referred to as “junk DNA” or even “parasitic DNA”, but it probably plays an important role in evolution. One piece of evidence for this is that RTEs of recent origin (those unique to primates) are a lot more active and mobile. They’re the part of us that is presently evolving. John Sedivy of Brown University reported that senescent cells – cells that have depleted their telomeres – are far more likely to have active RTE’s. These DNA segments make RNA copies of themselves which can then be “retro-transcribed” back into the chromosome, with disruptive consequences. (Transcription = DNA→RNA, part of the path by which chromosomes control the cell; Retro-transcription = RNA→DNA, an unusual and often pathological process)    Read more

 

Retinoic Acid promotes regeneration of damaged tissue

Retinoic Acid is an ingredient in prescription cremes which treat acne and also aging skin. Malcolm Maden from University of Florida reported that retinoic acid promotes regeneration generally. Read more

 

Genetic therapy is much advanced

Frank Church of Harvard reported on the state of the art in gene therapy. Fourteen years ago, the first gene transplant experiments resulted in death of a (very sick) teen patient, and set the field back several years. But advances in the interim make it possible now to insert a gene safely into a large number of cells of a lilving body, and target them to a precisely specified position on a chosen chromosome. This is done using CRISPRs, which are short stretches of RNA with a distinctive palindromic pattern, used by viruses to find the right place to insert themselves into a host genome.
Read about CRISPR
Read about Gene Therapy

 

Plasticity of the brain

Jean Hébert of Einstein Medical Center in New York is working to inject neural stem cells into the brain, to grow new nerves. This might seem like an impossible challenge. Nerve cells regenerate at a rate lower than any other cell type in the body, and even if we got them to regrow, how would they come to carry the knowledge and skills that we have acquired during a lifetime? Hébert reports a hopeful and amazing fact: In patients with brain tumors that destroy function in one part of the brain, another part picks up the function smoothly and without noticeable disruption. This has been noted with fMRI studies based on Boca’s area, which houses language.   Read more

 

Growing a liver on a lymph node

There is a long waiting list for liver transplants. In the US, 90% of patients with liver failure will die before they get a transplant. Some have proposed transplanting livers from pigs. Eric Lagasse of Wake Forest Inst for regenerative medicine has another idea. He has had success growing new livers from stem cells in the patient’s body. Liver progenitor cells are implanted in a lymph node, which seems to provide a favorable environment for growth. In mouse models, 70% are able to grow a functional liver “ectopically”, meaning in a part of the body where it does not belong.
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