Meryl Comer: Now when you study longevity, Dr. Guarante, you’re the upside. When you look at from your studies at a cellular level what are you looking for and what is the conversation between you and perhaps Dr. Arancio?
Dr. Guarente: Well I think that we come in a from a very simple position of what causes aging and are there any genes that control aging and that and that is how we have tackled this problem in first simple systems—yeast, fruit flies. And we were able to identify genes that we think work in all systems including humans to regulate aging and to give you an example that will tie it directly to what Dr. Gandy was talking about: one of the most important classes of proteins that have come out of these studies in aging are called sirtuins and they affect aging in a broad spectrum of organisms. Now, we’re studying them in mammalian systems and in particular in diseases because our premise is that diseases that occur late in life have aging itself as the trigger and if we could attack the aging component of the disease we can treat the disease. So this is just the opposite of taking a focused direct approach on the particulars of a disease and saying: let’s attack the aging, the underlying component and thereby ameliorate the disease. So it turns out in studies we’ve carried out in the past few years in my lab on Alzheimer’s disease in mice that one of the mammalian sirtuins called SIRT1 directly affects one of the components that Dr. Gandy was talking about; the plaques. And it reduces the protein that makes these plaques, which is called A-beta amyloid and so that was a very striking finding that we published. Now unknown to me two weeks later a paper from a different lab occurred that showed just in an independent study that SIRT1, the same sirtuin, also reduces the tangles and the tau protein, so that to me is very striking because we’re coming from a very, very simple point of view of aging and we end up targeting the two components that go awry and are at the basis of the etiology for Alzheimer’s disease, the plaques and the tangles, so I think to my mind that really justifies the idea that studying aging will have direct relevance to these diseases and, in particular, Alzheimer’s.
Meryl Comer: All right, well let’s look at that issue of the beta amyloid in the tau because it is very controversial now within the research field. Dr. Gandy?
Dr. Gandy: Well the strongest clues for Alzheimer’s, for how Alzheimer’s begins comes from the rare form that are entirely genetic. Out of all of Alzheimer’s, about 3% is entirely genetic. We know exactly which genes have the mistakes and what the mistakes are and how they exert their actions. And in every case those all point to this material called amyloid. It’s normally made by all cells all throughout the body, all throughout the lifespan. For reasons we don’t understand in certain regions of the brain it changes its shape, forms these sort of clumps that are poisonous to nerve cells.
Meryl Comer: And yet recent research has indicated that people who age well do have the beta amyloid in their systems. Is that correct?
Dr. Gandy: Well so the other side of the issue is how susceptible one’s brain is or one’s nerve cells are to amyloid poisoning. It’s clear that there are people who have all the pathology, all the pathological hallmarks of Alzheimer’s disease on the day that they die, but they are not demented. So it’s clear that they have resisted that poisoning, that toxicity from the amyloid.
Meryl Comer: Dr. Troncoso.
Dr. Troncoso: Yeah, I think that is a very good point. In fact, the work that I've done in the lab in recent years have focused precisely on that issue. Fortunately I've been able to work with the Baltimore Longitudinal Study of Aging conducting autopsies in patients who some of them are perfectly normal, others ones who have dementia. And in examining the brains of those individuals who were normal has been very surprising to us that a substantial number have a severe amount of the same lesions that Dr. Gandy was mentioning, plaques and tangles. And we have begun to examine and trying to find out what may be the difference. Why are they resilient to the disease? And we have found already some changes. For instance, some of these subjects, part of the brain, some of the nerve cells, are larger. So there is an element of compensation that allows some subjects that have the disease, that have these abnormal proteins, to be resilient at least for awhile. We don’t know if they’re going to be resilient 20 years down the road.
Meryl Comer: Let me just ask you about that and let’s talk about the human dynamic. Many people, smart people hide out in this disease a long time, because I understand it the hippocampus goes into overdrive and they fight harder and harder to keep up. Is that what you’re describing from a human side or...?
Dr. Troncoso: It’s the equivalent. This concept that you can resist the disease is being identified from many angles, like different men touching an elephant. There is information from the imaging, from functional imaging that individuals that as they get older, engage more brain regions to accomplish the same task, but they are able to accomplish the task. You can find where you put your keys or your checkbook. You may need to use more brain though for that. There is imaging studies that show that the hippocampus in these individuals who are able to resist the disease are larger, so there is evidence from many different perspectives that some individuals are able to resist the disease and if we can identify what are the mechanisms to do that it may contribute to prevent or to alleviate the disease.
Meryl Comer: Dr. Gandy, yes.
Dr. Gandy: There is actually conversation in both directions. The synapses and the signals control how much amyloid is made and in turn, as Dr. Arancio has shown, the amyloid itself can control the excitability of the nerve terminal of the synapse. So there is a very important conversation and the normal physiology of that conversation is very poorly understood.