Fight Aging! Newsletter, August 6th 2018

Do you think there are disproportionately many people from computer science in aging research these days?

There are a lot, and there are lots of people who are supporting it. Most of our supporters are, in one way or another, people from computer science or from mathematics, engineering, or physics. I think the reason why that has happened is actually very similar to the reason why I was able to make an important contribution to this field. I think that people with that kind of background, that kind of training, find it much easier to understand how we should be thinking about aging: as an engineering problem. First of all, we must recognize that it is a problem, and then we must recognize that it is a problem that we could solve with technology. This is something that most people find very alien, very difficult to understand, but engineers seem to get it more easily.

Can you give a bit more background on when you founded SENS and what SENS is?

The year in which I switched fields from computer science properly is probably 1995. For the next five years, I was basically just learning. The big breakthrough came in the summer of 2000 when I realized that comprehensive damage repair was a much more promising option then what people had been doing before. Since then, it has been a matter of persuading people of that. There were a few years when I was just ignored and people thought I was crazy and didn't think I made any sense. Then, gradually, people realized that what I was saying was not necessarily crazy. Some people found it threatening, so in the mid-2000s, I had a fair amount of battles to fight within academia. That's normal; that's what happens with any radical new idea that is actually right, so that happened for a while. This decade, it's been rather easier. We founded the SENS Research Foundation; we've started getting enough donations into the SENS Research Foundation to be able to do our own research, both within our own facilities as well as funding research at universities and institutes. Gradually, this research had moved far along enough that we could publish initial results. Over the past two or three years, we've been able to spin off a bunch of companies that we have transferred technology to so that they can actually attract money from investors.

Why do so few people have a sense of urgency that we need to do everything possible to combat aging within our lifetimes and not centuries to follow?

There are two answers to that. The David Botstein answer, the Calico answer, is that they just don't understand the idea of knowing enough. People who work on basic science understand how to find things out, but that's all they understand. For them, the best questions to work on are the questions whose answers will simply create new questions. Their purpose in life is to create new questions rather than to use the answers for a humanitarian benefit. They don't object to humanitarian benefit, but they regard it as not their problem. You can't change that. Botstein is a fantastic scientist, but he's in the wrong job at Calico.

The other part of your question, why people, in general, do not regard aging with a sense of urgency, has a different answer. People weigh up the desirability and the feasibility. Remember that everyone has been brought up to believe that aging is inevitable, I mean completely inevitable in the sense that stopping it would be like creating perpetual motion. If the probability of doing something about this thing is zero, then the desirability doesn't matter anymore. So, under that assumption, we really ought to put it out of our minds and get on with our miserably short lives. That's all we can do. It is learned helplessness, and it's a perfectly reasonable, rational thing to be thinking until a plan comes along that can actually solve the problem. That only happened quite recently.

The more interesting question is when will humanity actually conquer aging?

It all depends on how rapidly research goes, and that depends on money. Which is why when people ask me, "What can I do today to maximize my chances of living healthy and for a long time?" I tell them to write me a large check. It's the only thing one can do right now. The situation right now is that everything we have today - no matter how many books are written about this or that diet or whatever - is that basically, we have nothing over and above just doing what your mother told you: in other words, not smoking, not getting seriously overweight, and having a balanced diet. If you adhere to the obvious stuff, you are doing pretty much everything that we can do today. The additional amount that you can get from just any kind of supplement regime, diet, or whatever is tiny. The thing to do is hasten the arrival of therapy for the betterment of what we have today. That's where the check comes in.

Do you see any increase in funding for longevity research over the past 10 years?

Things have certainly improved. I mean, there's more money coming into the foundation, a little bit more money, but there's a lot more money coming into the private sector, into the companies I mentioned and other companies that have emerged in parallel with us. The overall funding for rejuvenation biotechnology has increased a lot in the past few years, and we need it to increase a lot more. The private sector can't do everything, not yet, anyway. There will come a time when SENS Research Foundation will be able to declare victory and say, "Listen, everything that needs to be done is being done well enough in the private sector that we no longer need to exist." For the moment, that's not true. For the moment, there are still quite a few areas in SENS that are at the pre-investable stage where only philanthropy will allow them to progress to the point where they are investable.

Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved mechanisms of aging. Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia.

The nematode Caenorhabditis elegans also exhibits age-dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age-dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age-dependent functional decline commonly observed in C. elegans.

Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short-lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long-lived animals such as humans and rhesus monkey and possibly in rodents.

The accumulation of acquired mitochondrial genome (mtDNA) mutations with aging in somatic cells has been implicated in mitochondrial dysfunction and linked to age-onset diseases in humans. Here, we asked if somatic mtDNA mutations are also associated with aging in the mouse. MtDNA integrity in multiple organs and tissues in young and old (2-34 months) wild type mice was investigated by whole genome sequencing.

Remarkably, no acquired somatic mutations were detected in tested tissues. However, we identified several non-synonymous germline mtDNA variants whose heteroplasmy levels (ratio of normal to mutant mtDNA) increased significantly with aging suggesting clonal expansion of inherited mtDNA mutations. Polg mutator mice, a model for premature aging, exhibited both germline and somatic mtDNA mutations whose numbers and heteroplasmy levels increased significantly with age implicating involvement in premature aging. Our results suggest that, in contrast to humans, acquired somatic mtDNA mutations do not accompany the aging process in wild type mice.

I'd like to thank Aubrey de Grey for inviting me to this wonderful conference, because aging is still the biggest risk factor for Alzheimer's disease. There are 35 million cases in the world today, and another 200 million people are walking around today who will get this disease over the next 30 years. So solving this one is like curing cancer ten times over.

Let's start at the beginning. In 1901, a German psychiatrist working at the Frankfurt asylum had this patient Auguste Deter. Alois Alzheimer was her doctor. She was 51 years old and severely demented; confused, disoriented, paranoid. She couldn't make any new memories. He followed her for five years until she died, and then he took her brain to the Kraepelin lab in Munich, where they discovered the pathology that underlay her condition. He wrote up a paper for that, a small paper, "On a Peculiar Disease of the Cerebral Cortex." It wasn't until a year later that Kraepelin wrote his textbook and mentioned the case, and he referred to it as "Alzheimer's disease." That is how it got its name - he didn't name it after himself.

The most obvious pathological feature, on a gross level, of Alzheimer's disease is a several atrophy or wasting of the cerebral cortex. It is due to the death of billions of neurons. If you take a section of that and you cut it up you find the two pathological features that they identified in Kraepelin's lab. Firstly there are plaques, tiny waxy deposits of amyloid-β protein and some other things, but mostly amyloid-β. Secondly, neurofibrillary tangles. These are the insoluable remnants of the cytoskeletons of neurons that have died. They are a very good marker for where the cell death is happening in the brain, but neurofibrillary tangles are something that sick neurons make. So it doesn't really tell us why they are sick, just that there were sick neurons there.

Amyloid has been the center and a preoccupation in Alzheimer's disease research for 25 years. Unfortunately it has not gone so well. It has been an unbroken string of failed clinical trials, costing 20-30 billion in private and public funding - and the bloodletting continues to this day. In just February of this year, two companies dropped out of their Alzheimer's development program. Close to 1800 clinical trials have been conducted on something related to Alzheimer's disease. Do you know how many of those trials have slowed or stopped the progression of Alzheimer's disease? Zero. Not a single one. That is what I call a systematic error. So a few years ago I began to apply Occam's razor to this, looking for a more simplistic solution. Is there something basic that we are missing, something that can account for the age-dependent incidence of the disease? Something that accounts for the higher risk for people who have traumatic head injuries, and the near certainty that people with specific mutations will develop the disease at an early age, just like Auguste Deter.

I'm going to need to use a little neuroanatomy here, but I'll try to keep it simple. At the top of the slide here we have the right halt of the cerebral cortex, the right is the front and the left is the back. The image below that, since it is just the half, is what it looks like on the medial surface - on the inside. The last image is what it looks like from below. Here we have three columns of such images for the three stages of Alzheimer's disease, early, middle, and late. The coloration is neurofibrillary tangle staining. If you notice on the left hand side, early stage Alzheimer's, the small orange portion of neurofibrillary tangle staining is the specific area where the pathology starts. It is almost like a little campfire; it starts off with a spark that smoulders a bit and then it explodes - it goes to other regions of the brain.

But it starts here, and this is called the medial temporal gyrus. It has the hippocampus in there, and big parts of the olfactory system. So there is something peculiar about this area. No other animal gets this disease, and in humans it starts in this one specific area. This is actually a different part of the cerebral cortex. In the early Alzheimer's images, the unstained yellow area is the neocortex, a six-layered neocortex. But the stained areas with neurofibrillary tangles are allocortex, three layer and five layer cortex. They are a more ancient part of the brain. What is it about this part of the brain that seeds Alzheimer's pathology, seeds the deposition of amyloid-β in the interstitial spaces of this region of the brain?

I think it comes back to the evolutionary origin. Here is an image of an alligator brain. The blue area is where the olfactory system is. It used to be a third of the forebrain - very important. If we look at other animals, we can see that in most mammals it is very large, because it is important for smell, which is important for survival, breeding, and evolutionary fitness. But in humans, notice how small the olfactory system is in the brain. It is just a tiny thing, and sits just below the prefrontal cortex, where executive function and abstract reasoning happen. So it is almost as it there was a turf war for space, and the olfactory system lost. So we think very well, but we can't smell very well. This is my dog Rex; when I take him for a walk, he smells as if it is an 80" plasma ultra-high-definition TV, and I smell like it is a little 1950s black and white with the fuzzy lines and stuff - a dog is 700-800 times better than the average human in sense of smell.

Now, the olfactory system is where Alzheimer's disease starts. In the image, these are the olfactory bulbs here, the little bulbs. So what is it about this area that seeds Alzheimer's pathology? I think it might have to do with the clearance of interstitial spaces. Here is an allegory. Think of a forest; there is a little stream in the forest, and leaves fall down from the trees. If they fall on the ground, they sit there and they rot. If they fall into the stream it carries them away. Later in the summer, the stream starts to dry up, and the leaves keep falling in. Eventually it hits a point at which the water can't carry them away, and then they form mats - or plaques. So I think it has to do with the clearance of the tissue.

In most of the body this is done in the following way: capillaries have these tiny holes, or fenestrations, or some kind of gap between the cells. Blood plasma comes out of these holes, and enters the interstitial compartment, where it becomes interstitial fluid. It passes slowly through there, picks up soluable macromolecules, maybe pieces of apoptotic cells, and other debris, and carries it along to the lymphatic vessels. They take it up, lymph nodes eventually taking it back to the bloodstream. Of course any cancer cells will also take this route, and that his how they so frequently wind up in the lymph nodes.

But in the brain, this system doesn't exist. The blood-brain barrier prevents any formation of fenestrations or gaps between the endothelial cells. The brain does it a different way. It has these large fluid-filled cavities called ventricles, and those have choroid plexuses that produce cerebrospinal fluid (CSF) - about half a liter per day per person. It percolates through the tissue, through the cortex, through all the spaces, and along the blood vessels, and it works its way up to the surface, to the subarachnoid spaces. From there some is resorbed, but some of it passes all the way down to the spinal cord, where you can get a lumbar puncture or a spinal tap to sample the CSF.

Now remember that I said that the olfactory system used to be a very big, very important part of the forebrain. CSF comes into the hippocampus, and works its way up to the surface at the medial temporal gyrus. But then it goes along the olfactory route towards the olfactory bulb, not towards the spinal cord. In this diagram, here is the medial temporary gyrus; fluid comes in, goes towards the surface, goes towards the front, and there is a rudimentary cone here - the lateral olfactory stria. This is a loose fiber bundle, and the CSF passes through little channels in there, along past the basal forebrain, and to the olfactory bulb.

Then what happens to the fluid? Well, here is an image of the interior of a skull, looking downwards. The front is at the top, the back is to the bottom. There are two little depressions or pockets, olfactory fossa, in the front of the skull. The olfactory bulbs sit in there, and the CSF drains through. In this cross-section figure, we can see the olfactory bulbs on top, a small gap, and below the cribriform plate and then nasal mucosa. Here are the olfactory nerves, sending information to the olfactory bulb about the odors they perceive. But there are gaps in there, and the metabolite-laden CSF makes its way through into the nasal mucosa, where there are plenty of lymphatic vessels. For anyone who has ever had a nasal vaccine - the presence of so many lymphatic vessels in the nasal mucosa is why this delivery method is used.

The cribriform plate is a natural choke point for the clearance of this fluid from the brain region where the disease starts. Here is an image of a 26 year old skull, and a CT scan of the same. You can see that there is some thick bone in the cribriform plate here, but not very much. Here is a CT scan of the same region of an 80 year old skull, and you can see that there is a lot more bone deposition in the cribriform plate. This structure at the top of the image is a piece of bone that sticks up, and I'll show you more of it in a minute. It is called the crista galli and notice how much bigger it is in the older person. We have continuing bone deposition in this area. One of the effects of that is that it closes off the holes, the apertures, reducing the ability to clear the CSF.

Here is an image of a CT scan of the skull, and this is seen from the front. The cribriform plate is on the bottom here, and this vertical structure is the crista galli. Notice it goes down the middle, right here, all the way and connects up with the bone in the middle of your nose, the nasal septum. The second image shows a cribriform plate from the interior of the skull. You can see the apertures there. What we've been doing at Leucadia is high resolution micro-CT imaging of about 70 human cribiform plates. These are taken from control subjects at different ages, and from Alzheimer's patients.

The image here is of a 26-year-old control cribriform plate. I actually have a 3-D print with me, as we do a lot of that as well. You can see the holes, plenty of apertures. There is a little thick bone, but lots of apertures - Swiss cheese, practically. If we look at 70-year-old control, we can see that there is a bit of a bony veil that has developed, and there are not so many apertures in here. There is a little bit of bone deposition. If we go a little further, and look at an Alzheimer's disease cribriform plate, notice the big bony veil convering pretty much all of the apertures at the very back of the olfactory fossa.

See also a big bony area in the middle, because this cribriform plate is uneven. The crista galli is in the middle: if you break your nose, it is going to deflect the crista galli, and when it heals there will be extra bone around the injury. So in this case we can tell that it has been deviated due to past injury, and thus there is thicker bone on that side. So it seems that if you injure the cribriform plate, it is going to affect this system. This next image is the cribriform plate for a different Alzheimer's patient. You can see that the channels in the middle are different, but the big bony veil is similar. So we are talking about how much capacity there is to drain the CSF, and that seems to be different in Alzheimer's patients.

We are carrying out these high resolution micro-CT scans on cadavers, but we want to start doing them on humans, because we want to be able to relate what we see in the high resolution samples with what we will see in a lower resolution clinical sample. We do that, we'll get our scans, and the hard-working interns at the company are going through and segmenting these files: I have to go through and say that is bone and that is other tissues. We produce these 3-D models of the cribriform plate, like the one I just showed you, and if we take just the one aperture and expand it like this diagram here, we can see it is made up of dots, and each dot has an (x,y,z) coordinate. We get a big file that contains thousands upon thousands of these coordinates, and that's how we're matching up the samples, using computers.

If we do this, what we should be able to accomplish is, theoretically, when we are all finished with our database, is look at someone's scan and determine the theoretical CSF flow capacity. If we can do that, then we can use CT scans to say, well this person obvious has a lot of occlusion here, or this person is fine. This will come in very handy for mild cognitive impairment, which is the pre-dementia state. Only about 10% of those patients progress on to Alzheimer's disease. The big question has always been which ones? If we can do these scans and say this one and that one and so on, it is going to be a big help. It could also be part of an annual wellness assessment for seniors. Maybe they get a scan every two years or five years, and we can actually watch the progression of ossification, and calculate how long it is going to be before they hit the critical threshold.

The bone is kind of only part of the story, because the other part is the soft tissue. This image is the highest resolution MRI ever done of a human cribriform plate. What we see here is the soft tissue is blue and the bone is a firey color. You can see where the apertures are, but that's not quite good enough, because there are so many apertures, a couple of dozen apertures, and some of them have blood vessels, some of them have nerves, some of them probably have the channels for CSF, but we need to know which are which. So we came up with another method: we figured out a way to enhance the staining, so that we could use CT to resolve bone and nerve and other tissues in the micro-CT images. Then we go in and digitize it. In this digitized image you can see the bone, the nerve, and these blue things here are the fluid-filled conduits where the CSF is actually flowing through. We can use this with our database to figure out how much CSF flow capacity there is.

Here is another digitized image showing the same, you can see the nerves in orange and the flow channels in blue. We can remove the bone from the image to show just the structure within. Now this yellow structure that is something else; it is a little interesting and nobody else have ever seen that before. These are actually channels within the bone, CSF conduits that are connected to the soft tissue drainage channels. It is almost like an equilibriation of the CSF flow mechanism. These CSF conduits in the bone, we can see them in the control cases, but looking at the Alzheimer's patients they are almost completely gone. We are losing these conduits and we're also getting ossification. So there is really something going on here with the CSF flow.

The proof of concept we are doing for this is we are blocking the cribriform plate in ferrets. It turns out that mice and rats, for a number of reasons, are probably the worst model you can pick for Alzheimer's disease. It is ironic, because the NIH has been very draconian about "you must use mice." In this picture you can see our team of human neurosurgeons, who brag now that they are the greatest ferret neurosurgeons in the world. The ferret pictured here has had surgery a few months before; the surgeons go in through the top of the skull, go into the nasal cavity, make a little window, peel the tissue off the cribriform plate, and put bone cement on there to block it up. We want to see after six months do we get plaques and tangles, hopefully so and that would be great. But in the meantime we're doing behavior studies. Pictured here is the maze that they run through. We are assessing them every two weeks, and when we finish this study we'll put it all together.

It is one thing to tell someone that we have done a scan and you are going to get Alzheimer's disease in five years or seven years, or you have a very high risk because of your cribriform plate. It is another thing to be able to do something about it. This slide is an image from Greek mythology, the water nymph Arethusa, and she attracted the attention of a river god, and she couldn't get away from him. Artemis saved her by turning her into a hidden underground stream. That is what we want to do; we want to make a hidden under-the-tissue channel to drain the fluid from this area. We call it Arethusta.

Here is a simple diagram. We go up through the nose, the cribriform plate is up there at the very top of the nasal cavity, and we put in the device. This is a very old version of the device. We have much newer, better ones, but it is in the patent, which is publicly available. What we feel we'll do is put the shunt in maybe in people who have mild cognitive impairment. That should actually reverse their mild cognitive impairment (MCI), because the MCI is happening because the amyloid-β has become oligomeric, which is toxic to synapses. So the synapses aren't working as well. This is even before the formation of plaques. If we restore the flow, we should be able to reduce the level of oligomeric amyloid-β and hopefully prevent the disease from progressing to Alzheimer's disease. That is our plan.

We think it is minimally invasive, although we do have neurosurgeons do it because we are puncturing into a part of the brain, and we have to be very careful about that. We think it should be pretty straightforward, and the trial, since we're targeting MCI, isn't going to be the 10 or 20 year trial for an Alzheimer's study. It will only be a couple of years, because we should see the effects in a matter of weeks to months. Then hopefully five years later they don't progress to Alzheimer's disease.

So in summary, I talked about the cribriform plate as the final outlet for CSF in the region where the disease starts. It is a natural chokepoint. We saw age-dependent changes in the cribriform plate, and the Alzheimer's patients show more occlusion. Then there are the flow channels, the fluidics. Looking at these flow channels is just a lot of work because these files are enormous, and it takes weeks and weeks to go through one and identify all of the channels and all of the nerves. But we are making good progress. Then what we really want to do is use all of our information to make a diagnostic algorithm that will work with an appropriate CT scan from anyone, and figure out where they are in the spectrum - and then treat MCI.

How do you think we age; are we programmed to die, do we wear out, or is the truth a mixture of both?

I don't think we wear out. Humans and complex animals are made of cells and molecules that, by and large, have some turnover; we can replace most of our components, so I don't think it's correct to see aging as wearing out, at least not in complex animals like humans. That said, I do think that some forms of cumulative damage contribute to the aging process, such as DNA damage. I also think that there are programmatic aspects to aging. That is, I think that genetic programs coordinating some aspects of growth and development persist into adulthood and become detrimental as forms of antagonistic pleiotropy. It is probably a combination of molecular damage and the inadvertent actions of genetic programs that causes aging.

There seems to be an increasing suggestion in academia that directly targeting the underlying aging processes is the most promising strategy.

Absolutely; this is something that biogerontologists have been arguing for a very long time. I also think that the graying of the population means that there is a growing awareness of the need to develop approaches to tackle the process of aging and associated pathologies.

There also seems to be an increasing amount of investment in rejuvenation biotechnology in the last year; what has happened in science to encourage this commitment?

There's more than one reason to explain this recent excitement in anti-aging biotech. One reason is the aforementioned graying of the population, making anti-aging interventions commercially very appealing. In addition, the discoveries of the past couple of decades showing that the process of aging is plastic and can be manipulated in model organisms has generated tremendous excitement. Even in mice, we can tweak one gene and extend lifespan by nearly 50%, retarding a multitude of age-related pathologies. If we could do that in humans, that would mean making people not only live longer but stay healthy for longer. Again, from a financial perspective, that would have huge implications, and any company that were to develop a true anti-aging intervention would make huge profits. My recent review of the business of anti-aging science discusses this topic in more detail.

What is the biggest bottleneck to progress in aging research, in your view?

Most scientists would say lack of funding, but while having more funding would certainly accelerate progress, I think it would only help so much. This is because experiments in aging, and potential human clinical trials, are intrinsically time-consuming. That is not going to change with more funding. I would argue that the biggest bottleneck to progress in aging is the nature of the aging process itself in that it takes quite a long time, which, in turn, means that studies and trials will also take a long time.

Historically, infectious diseases were the cause of morbidity and mortality. Infectious disease arguably continues to be the major driver of morbidity and mortality however this connection is largely ignored because of the occult nature of many of the causative agents and the cryptic cause and effect between organism and disease. The concept of evolutionary fitness actually points to infection as being the major cause of disease in modern society. Genetic traits that may be unfavorable to an organism's survival or reproduction do not persist in the gene pool for very long. Natural selection weeds them out and any inherited disease or trait that has a serious impact on fitness must fade over time. Therefore, when diseases have been present in human populations for many generations and still have a substantial negative impact on people's fitness, they are likely to have infectious causes.

Immune system vitality may be the most important risk factor in any chronic disease including Alzheimer's. Apart from symbiotic coexistence of human with micro-organisms, disease causing organisms breed in man-made unhygienic conditions of air water and soil. People with low immunity, weak, and living in unhygienic conditions are at greater risk for contracting the infections from surroundings. This model of disease fits equally well with Alzheimer's and other chronic diseases but has been limited because source of the infection is less obvious and diagnosis is not frequently enough made or considered.

Chronic inflammation is considered a cause of chronic disease, including Alzheimer's. Chronic inflammation continues to be blamed for tissue damage but this complex cascade, stimulated by internal and external mediators, results in the release of danger signals that promote immune responses to antigens. Chronic, occult infection is a significant stimulator of chronic inflammation. Any chronic disease, then, is potentially a measure of the stress on the biological system and its ability, or lack thereof, to cope.

Chronic disease incidences, including Alzheimer's, increases with older age and are linked to immunosenescence. Numerous studies show that the pathology of Alzheimer's disease is present decades before a clinical diagnosis of dementia can be made. Predisposition to Alzheimer's, therefore, is established prior to the acceleration of immunosenescence that starts around age 65. The vulnerability to disease due to an immature immune system during the ages 0-5 is also relevant. It is during these times that the antecedents of Alzheimer's and other chronic diseases, specifically occult infections, may opportunistically infiltrate such vulnerable hosts only to express as disease across the spectrum of time and lead to the a significant upswing in Alzheimer's.

Significant reductions in the risk of mild cognitive impairment (MCI), and the combination of MCI and dementia, have been shown for the first time through aggressive lowering of systolic blood pressure. Researchers reported preliminary results related to risk of dementia and cognitive decline from the Systolic Blood Pressure Intervention Trial (SPRINT). SPRINT is a randomized clinical trial that compared two strategies for managing high blood pressure (hypertension) in older adults: an intensive strategy with a systolic blood pressure goal of less than 120 mm Hg versus a standard care strategy targeting a systolic blood pressure goal of less than 140 mm Hg. Previously, SPRINT demonstrated that more intensive blood pressure control reduced the risk for cardiovascular morbidity and mortality.

SPRINT Memory and Cognition IN Decreased Hypertension (SPRINT MIND) examined whether treating to the lower blood pressure target reduces the risk of developing dementia and/or MCI, and reduces the total volume of white matter lesions in the brain as shown by magnetic resonance imaging (MRI). Study participants were 9,361 hypertensive older adults with increased cardiovascular risk (based on the Framingham risk score) but without diagnosed diabetes, dementia, or prior stroke. Participant mean age was 67.9 years (35.6% women) and 8,626 (92.1%) completed at least one follow-up cognitive assessment.

Recruitment for SPRINT began in October 2010. At one year, mean systolic blood pressure was 121.4 mmHg in the intensive-treatment group and 136.2 mmHg in the standard treatment group. Treatment was stopped in August 2015 due to cardiovascular disease (CVD) benefit after a median follow up of 3.26 years, but cognitive assessment continued until June 2018. In SPRINT MIND, the researchers found a statistically significant 19 percent lower rate of new cases of MCI in the intensive blood pressure treatment group. The combined outcome of MCI plus probable all-cause dementia was 15 percent lower in the intensive versus standard treatment group.

Low back pain (LBP) is one of the most common causes of activity limitations, neurological deficit, and disability in affected individuals. Intervertebral disc (IVD) disorders contribute to LBP and neck pain in multiple ways with few available treatments. New approaches are urgently needed for the treatment of degenerative disc disease (DDD). In the past decades, diverse strategies have been developed aiming to ameliorate IVD degeneration and promote its regeneration. While considerable progress has been achieved in treatment and regeneration of nucleus pulposus (NP) in the center of the disk, much less is achieved in that of the surrounding annulus fibrosus (AF). As a crucial supporting component in the biomechanical constitution of IVD, the structural and mechanical integrity of AF is highly essential in confining NP, and tears or fissures in AF are closely associated with the onset and development of DDD.

Various biotherapies have been proposed, including molecular therapies, nucleic acid-based therapies and mechano-regulated cell based therapies. These therapies, aiming at supplementing biologics including growth factors, genes, and cells in AF, have shown promising results in vitro and in vivo. Nevertheless, their clinical uses still remain a major concern due to the short-term efficacy and insufficient stability of them. These limitations may be, at least partially, overcome by biomaterials-based tissue engineering (TE) using a combination of cells and biomolecules to restore AF anabolism.

Scaffolds are one of the most important elements in AF TE by providing appropriate mechanical properties, adequate space, and biochemical cues for seeded cells to grow, differentiate, and produce extracellular matrix (ECM) to regenerate AF tissue. Various kinds of scaffolds have been designed for AF engineering. The scaffolds can be made from natural materials or synthetic materials. These scaffolds can be fabricated and processed using various techniques depending on the desired structure characteristics and mechanical properties of the final engineered tissue. Among the techniques, electrospinning is preferred for AF TE by researchers for its ability to produce micro- and nanofibers which largely recapitulate the structural characters of native AF tissue. The mechanical properties of scaffolds remarkably affects the biochemical and biomechanical properties of cultured AF-derived stem cells and the ECM they produce.

Pharmacological treatment with FGF21 ameliorates age-related metabolic disorders such as insulin resistance, dyslipidemia, and obesity in rodents, and pilot studies in humans indicate that treatment with an FGF21-analog has beneficial effects on hyperlipidemia and body weight. Sustained increases in FGF21 levels attained by transgenic overexpression of FGF21 extend the lifespan of mice, suggesting that FGF21 is a pro-longevity hormone. Circulating FGF21 levels in humans increase with age from 5 to 80 years in healthy individuals independently of body composition. In contradiction, low levels of FGF21 are related to healthy aging in centenarians. In addition, endurance exercise in elderly individuals reduces FGF21 levels.

Thus, it has been suggested that the increases in FGF21 that parallel aging are related to the appearance of an age-related FGF21-resistant state, as has been proposed in metabolic diseases. In obese and diabetic patients, FGF21 levels are abnormally elevated and an FGF21-resistant state has been claimed to accompany these pathologies. In this study, we analyzed FGF21 levels and alterations in the expression of genes encoding components of the FGF21-responsive molecular machinery in adipose tissue from aged individuals so as to ascertain whether altered FGF21 responsiveness that develops with aging jeopardizes human health and/or accelerates metabolic disturbances associated with aging.

We studied a cohort of 28 healthy elderly individuals (≥70 years) with no overt signs of metabolic or other pathologies and compared them with a cohort of 35 young healthy controls (≤40 years). Serum FGF21 levels were significantly increased in elderly individuals compared with young healthy controls. This is in line with previous reports describing an increase in FGF21 levels with aging. Levels of β-Klotho, the coreceptor required for cellular responsiveness to FGF21, were increased in subcutaneous adipose tissue from elderly individuals relative to those from young controls, whereas FGF receptor-1 levels were unaltered.

Adipose explants from aged and young mice respond similarly to FGF21 "ex vivo". Thus, in contrast to what is observed in obesity and diabetes, high levels of FGF21 in healthy aging are not associated with repressed FGF21-responsiveness machinery in adipose tissue. The lack of evidence for impaired FGF21 responsiveness in adipose tissue establishes a distinction between alterations in the FGF21 endocrine system in aging and chronic metabolic pathologies. Either FGF21 resistance per se does not occur during aging or tissues other than subcutaneous fat are the actual source of such resistance.

Physical exercise has repeatedly been demonstrated to alleviate comorbidities associated with aging, and to contribute to reducing an individual's risk of developing neurodegenerative conditions such as Parkinson's disease (PD) or Alzheimer's disease (AD). Evidence has accumulated to suggest that exercise can ameliorate many of the symptoms of PD, not only the motor dysfunction, but also some of the non-motor symptoms (NMS), such as cognitive impairment and depression.

In order to decipher the cellular and molecular mechanisms underlying the potential beneficial effects of exercise in PD, it is necessary to employ animal models. The most common models used by the scientific community focus on replicating the motor symptoms of the disease, by applying a chemical lesion in order to cause degeneration of the dopaminergic pathway, which is responsible for controlling movement. However, such models are not useful for examining the NMS, which typically involve several different neurotransmitter pathways and multiple regions of the brain. A recently-developed animal model, involving induction of α-synuclein overexpression in the adult rat brain using adeno-associated viral (AAV) vectors, is widely considered to most consistently reproduce the pathological features and progressive neurodegeneration associated with human PD.

Adult male rats were given free access to running wheels in cages (voluntary exercise) from one week after administration of AAV-α-synuclein into the substantia nigra. We found that voluntary exercise had no effect on motor function or on dopaminergic neuronal loss in the substantia nigra. However, overexpression of α-synuclein significantly impaired the ability of the animals to perform hippocampal-associated cognitive tasks. This was associated with deficits in hippocampal neurogenesis, a form of neuroplasticity and a key cellular process underlying learning and memory. Importantly, voluntary exercise protected against this cognitive dysfunction, and this protective effect was mediated, at least in part, by alterations in neurogenesis levels.

This is the first study to date that has employed the AAV-α-synuclein model to investigate exercise as a therapeutic intervention, and its strength lies in the fact that this model is widely accepted to be the most similar to the progressive nature of the human condition. It must be appreciated that there are difficulties associated with measuring the effects of exercise in patients, as well as in animal models, that have problems with their motor function. Nevertheless, all of the available evidence suggests a growing rationale for including structured exercise programs as part of a patient's therapeutic regimen.

The last full day of the Alzheimer's Association International Conference saw scientists pack a room the size of an aircraft hangar in anticipation of a late addition to the scientific program. They came to see the data behind a tantalizing press release issued earlier this month, which had claimed that BAN2401, the anti-Aβ protofibril immunotherapy, reduced amyloid in early Alzheimer's disease and also slowed cognitive decline. The upshot? According to the results presented, the antibody appears to have done what it was designed to do.

Over 18 months, fibrillar amyloid fell in all treatment groups compared with placebo; indeed, plaques melted by a whopping 93 percent in participants on the highest dose. This dose was reported to have reduced cognitive decline by 47 percent as measured by the ADAS-Cog, and by 30 percent on the ADCOMS, a new composite measure to detect early cognitive decline. At 856 participants with mild cognitive impairment due to AD or mild AD, this trial is the largest one yet to post both amyloid reduction and a downstream benefit on symptoms.

Statisticians and clinicians who gathered in the hallways after the presentation were cautiously upbeat. "Overall the results are positive and the amyloid effect is impressive. I believe this antibody works. In summary, there is dramatic amyloid lowering, with some apparent slowing in decline at the highest dose. The field is clearly moving forward with the ability of a fourth drug to remove amyloid to a normal level, as measured by PET. Now with aducanumab, gantenerumab, and n3pg, BAN2401 has demonstrated reversal of amyloid plaques to normal levels, representing a milestone in the history of Alzheimer's disease."

Sarcopenia is a geriatric syndrome defined as the age-related loss of skeletal muscle mass and function, quantified by objective measures of muscle mass, strength, and physical function. One major risk factor for the development of sarcopenia is protein-energy malnutrition. A number of factors can lead to reduced protein intake in older age. Patients with sarcopenia are often frail (vulnerable to minor stressors) and the two concepts (frailty and sarcopenia) share an increased risk of adverse outcomes. Three large observational studies have supported an association between protein intake and muscle strength and mass, but multiple trials carried out in healthy, replete, older adults, without an exercise intervention, have been negative.

In those with suboptimal protein intake, the most promising results are for specific essential amino acids, particularly leucine, but also its metabolite β-hydroxy β-methylbutyric acid (HMB). Supplementation with these more targeted regulators of muscle protein synthesis (MPS) may be most effective for overcoming anabolic resistance in this cohort, especially if combined with exercise, a potent stimulator of anabolic response in muscle at all ages. Anabolic resistance refers to the phenomenon whereby older adults require a higher dose of protein to achieve the same response in MPS as a younger adult. The aetiologies and mechanisms for this are not understood, but we propose that the gut microbiome may be implicated in one or many of those suggested in the literature.

With age and frailty in particular, the resilience of the gut microbiome is reduced, as it becomes more vulnerable to medications, disease, and changes in lifestyle, with changed species richness and increased inter-individual variability. Ageing is associated with chronic inflammation, often referred to as 'inflammaging'. Here we suggest that this 'inflammaging', in combination with altered gut microbiome composition and/or diversity, leads to changes in protein metabolism, absorption and availability; ultimately contributing to anabolic resistance and therefore to reduced MPS and the development of sarcopenia.

It is possible that someone reading this now will be alive to see the resolution of a 1 billion bet between Jay Olshansky, a University of Illinois at Chicago professor of public health, and Steven Austad, chairman of biology at the University of Alabama at Birmingham. Eighteen years ago, the two friends began their discussion on an issue that long has intrigued scientists and laymen alike: What is the limit of the human life span? Austad, whose research focuses on aging, had made a bold prediction at an academic conference: In the year 2150, he said, there will be a 150-year-old human being. Olshansky, also an expert on aging, wasn't having it.

They decided to make it interesting. They each put 150 into an investment fund, and signed a contract specifying that the heirs of the winner will cash it out in 2150. Early published reports on the wager said the payoff would be from 200 million to 500 million given good market returns, but the men have since doubled their initial investments and they now estimate the final jackpot at roughly 1 billion.

Since they made wager in 2000, average human life spans have inched up. I asked Olshansky if, in light of the galloping progress of medicine on all fronts, he was having any second thoughts about his position. None, he said. If anything he's more certain than ever that his descendants - he has one grandchild so far - will be made fabulously wealthy. "There will certainly be breakthroughs that will slow many of the biological processes of aging. We'll be able to extend the number of years that people can live in good health but the brain is our Achilles heel. There's still no evidence to suggest that we'll be able to halt the effects of the daily loss of nonreplicating neurons, much less reverse it. We can replace hips, knees, hearts and so on, but we can't replace the brain."

Austad, too, believes more firmly than ever in his position. "We're discovering more and more ways every year to make mice live longer through drugs and diet. A 150-year-old person is only about 20 percent older than the current record holder, and we've found dozens of ways to extend the lives of mice by that much. Not all of them will work with humans, of course, but if any of them do, we're going to see dramatic results. All we have to do in the next 30 years is find drugs that dramatically slow the underlying causes of aging. If we give them to people approaching 50, some are going to reach the extreme of 150."

In the past, Alex Zhavoronkov claimed that he expected to live to be 150, but now he's more conservative. He's skeptical that we will see such drastic changes to the human lifespan quite so soon. There are too many hurdles left to clear, and he feels that today's political and economic climate isn't exactly conducive to expensive, experimental longevity research. To be clear, he does believe humanity will someday live that long, but not as soon as he thought. Someday, Zhavoronkov argues, we will build a future where humans can all live longer and healthier, enjoying productive lives well past the ages we never thought we'd reach at all. To get there, the powers that be will just need to shift their focus and decide that longevity is worth pursuing. And his company, along with others that are looking into big data, will forge ahead until that happens.

It's hard to argue that scientists shouldn't find ways to help people live longer. Zhavoronkov argues that longevity ought to be a fundamental human right - the right to live as long and well as possible. Living longer and healthier would help people enjoy a better quality of life, but it would also prevent or solve many of the problems facing our economy. Presumably, living longer will fix the economy because people will grow old without growing frail - our eternal descendants will spend less time at the nursing home and more time at the office. The economic argument is a compelling one for the people holding the purse strings for the grants that fund research, but so far it hasn't been enough for them to funnel money into the field, where Zhavoronkov thinks it's most needed.

"This is very frustrating. But this is the nature of today's society. People in the developed countries have most of their basic needs already satisfied but instead of focusing on securing the future, they focus on today's events. Clearly the governments and the people they represent have their priorities misplaced." In an ideal world, transformative changes will ripple through healthcare within ten to fifteen years, Zhavoronkov predicts. But he's disappointed that his company and other teams working on real, science-based, longevity research haven't gotten more hype. "The limitations on what we can do for longevity today come from our current understanding of technology and will not be there in the future. We need to focus on what is available today at the very cutting edge and take it to the next level."

Strong evidence shows that physical activity has beneficial effects on well-being, health, and longevity in older ages. The survival effect of physical exercise has received support by a large study of more than 40,000 athletes, which shows that the Standardized Mortality Ratio (SMR) for athletes compared to the standard population was 33% lower. There are also other studies showing that physical exercise decreases mortality. In one study it was found that jogging or brisk walking more than 7.5 hr every week was associated with a higher life expectancy. In another study, for a person engaged in more frequent physical activity, the mortality risk was about 25% lower than for those less frequently active.

The longevity effect of physical activity seems, however, in a number of studies, in which both light and intense physical activity levels have been used, to be U-shaped according to frequency and intensity. Some researchers have tried to establish a dose-response relationship between the amount of exercise and decrease of mortality. Assuming the existence of a U-shaped relationship, moderate activity levels seem most preferable. This assumption has also been empirically supported with regard to the relationship between the amount of exercise and cardiac morbidity, quality of life and cognitive functioning. In addition, people with more frequent moderate physical activity (MPA) were engaged in more cognitive activities. It has also been found that only one to two hours of jogging weekly decreased the risk by 71%.

Assuming the existence of a U-shaped relationship, it has been suggested that while the largest decrease in the risk of death takes place when going from zero to any moderate physical activity, more frequent and intense physical activity is beneficial only for a very small part of the population, such as trained athletes. In this study, a sample of 8,456 individuals aged 60 to 96 years, representative of the Swedish population, was included. Participants were followed from 2004 to 2015. The results show that 82.1% of the total sample performed MPA 2 to 3 times every month or more, and those were, in an 11-year perspective, more often still alive.

In comparison with other studies, the low frequency of MPA needed for an effect on longevity was remarkable, although low levels have been suggested previously. The results do not contradict the general recommendations of daily moderate physical activity, but the present results also indicate that health advantages, at least in terms of longevity, can be achieved by an even lower activity frequency. The previously made suggestion that the strongest difference in health outcomes can be observed between those not active at all and those performing any moderate activity is confirmed by the result of this study.

A new study using data from the Trinity Ulster Department of Agriculture (TUDA) ageing cohort study comprising over 5,000 individuals has found that a measure of belly fat (waist:hip ratio) was associated with reduced cognitive function in Irish adults older than 60 years. These findings have significant implications as the global prevalence of dementia is predicted to increase from 24.3 million in 2001 to 81.1 million by 2040.

Previous studies have found that people who are overweight do not perform as well on tests of memory and visuospatial ability compared to those who are normal weight. However, it is not well known if this is true in older adults. This is of concern within Ireland, as over half of the over 50s population is classified as being centrally obese, with only 16% of men and 26% of women reported to have a BMI (body mass index) within the normal range.

The researchers used data from the TUDA study, which is a cross-border collaborative research project gathering data from thousands of elderly adults in Northern Ireland and Ireland. They found that a higher waist:hip ratio was associated with reduced cognitive function. This could be explained by an increased secretion of inflammatory markers by belly fat, which has been previously associated with a higher risk of impaired cognition. On the contrary, body mass index (BMI) was found to protect cognitive function. BMI is a crude measure of body fat and cannot differentiate between fat and fat-free mass (muscle), thus it is proposed that the fat-free mass component is likely to be the protective factor.