In biology as elsewhere, nothing really lasts forever. Things break down and gunk builds up. Sadly, our most vulnerable organ in this regard is also the one that we can least do without: the brain.
As it ages, the brain becomes increasingly susceptible to degenerative, debilitating ailments including Alzheimer’s, Parkinson’s, and ALS (also known as Lou Gehrig’s disease). Scientists have found that virtually all such age-related neurodegenerative diseases—plus some others that strike earlier in life, such as the genetic disorder Huntington’s disease, and the prion infection Creutzfeldt-Jakob disease—are associated with the buildup of toxic gunk, in the form of abnormal protein aggregates. Researchers have uncovered evidence, too, that the brain’s innate defenses against these protein-waste buildups naturally tend to weaken with age. Unsurprisingly, then, dozens of academic and commercial laboratories are looking for ways to boost these waste-disposal systems in the aging brain, to ward off neurodegenerative disease—and perhaps more generally, to extend the brain’s working life. “It’s a very hot field now,” says Steven Finkbeiner, M.D., Ph.D., senior investigator at the Gladstone Institutes and professor at the University of California-San Francisco.
Protecting the brain from the hazardous debris of aging looks like quite a challenge. Indeed it seems miraculous that the brain already works as long as it does. The cells in most other bodily organs and tissues live only for days or weeks or years, and are replaced (from local stem cells) throughout a person’s life. By contrast, nearly all the neurons that an adult human carries in his or her head will never be replaced; they are meant to stay where they are for the person’s lifetime, which may last over a century. These neurons are living, working cells—little walled cities within each of which tens of thousands of proteins, fats, and sugars interact constantly. Such interactions generate waste matter, which neurons must manage, lest the waste accumulate and become toxic. Moreover, neurons frequently have to perform this waste-management feat over exceptionally long distances. The span of a single neuron’s input and output stalks (dendrites and axons) can be as much as a meter—hundreds of thousands of times longer than the neuron’s tiny diameter.
Some of the protein aggregates that are apt to clog the aging brain are zipped tightly together in what pathologists call an “amyloid” structure. The best known amyloid-forming proteins are amyloid beta and tau in Alzheimer’s disease, alpha synuclein in Parkinson’s disease, prion protein in Creutzfeldt-Jakob disease, and huntingtin in Huntington’s disease. ALS and fronto-temporal dementia often feature aggregations of TDP-43 protein, which are not amyloids but appear to be toxic to neurons nonetheless. These aggregates often show up in diseased brains as large, insoluble deposits—such as the amyloid beta plaques of Alzheimer’s—but scientists increasingly view the small, soluble aggregates of these proteins as the truly toxic ones.
Even if abnormal protein aggregates harm us only through specific diseases, we should expect them to have an impact on lifespan. After all, these diseases are significantly life-shortening and collectively common—it is estimated that nearly half of people 85 and older have Alzheimer’s, for example. But there are already hints that protein aggregates can speed our cognitive declines and shorten our lifespans, even without causing diagnosed disease. For example, in the summer of 2012 a team of researchers reported in Nature on an aggregate-related gene mutation they found in elderly Icelanders. Those in their sample who had this lucky mutation “had fifty percent greater probability of becoming 85 years of age than people who didn’t carry it,” says Kari Stefansson, M.D., the neurologist at Reykjavik-based deCode Genetics who led the team. Carriers of this mutation also seemed virtually immune to Alzheimer’s, and appeared to undergo a slower cognitive decline as they aged. At 90 they remained sharper on average than 80-year-old non-carriers. How did this beneficial gene mutation bring about such a result? Evidently by halving the enzyme-mediated production in the brain of the Alzheimer’s-linked amyloid beta protein—which in turn should have lowered the protein’s concentration in the brain, making it less likely to form amyloid aggregates.
Some scientists have found hints that in common, late-onset Alzheimer’s, overproduction of amyloid beta triggers the disease. Others have found a declining ability to dispose of the protein. Either way, boosting the brain’s ability to handle aggregation-prone proteins seems likely to help.
There is already striking evidence for this from animal studies. For example, as the UC-San Francisco laboratory of Cynthia Kenyon, Ph.D. reported in 2003, the lifespan of the roundworm Caenorhabditis elegans can be increased dramatically by reducing the activity of a key metabolic network, known as the insulin signaling pathway. This signaling pathway has a counterpart in humans, and can be reduced simply by fasting. A number of labs, starting with that of Andrew Dillin, Ph.D. at The Salk Institute for Biological Studies, have since shown that a big part of the life-extending effect of reduced insulin signaling seems to come from an improved protein-handling capability. “One of the things that the insulin signaling pathway does is to suppress a pathway that protects against the toxicity of aggregation-prone proteins,” says Ellen A. Nollen, Ph.D., a researcher in this field at the University of Groningen in the Netherlands. “There are now a lot of indications that if you activate only the latter pathway and increase protection against these proteins, the animals live longer.” These indications now include findings not just in worms but in mice too.
For many researchers, the focus now is on finding ways to boost the specific waste-disposal systems in the brain that protect it from harmful aggregates. Some, for example, are working on boosters of apolipoprotein-E (apo-E)—a fat-carrying molecule that plays a big role in amyloid beta disposal. Amyloid beta seems to want to stick to apo-E, and in a way that leaves the small protein relatively vulnerable to destruction by protein-cleaving enzymes. One common variant of apo-E, the ε4 variant, apparently does a poor job at grabbing amyloid beta, and has long been linked to increased Alzheimer’s risk and shorter lifespan. But whatever apo-E variant one has, increasing its levels should increase one’s rate of amyloid beta clearance in the brain. Gary Landreth, Ph.D., director of the Alzheimer Research Laboratory at Case Western Reserve University in Ohio, reported early in 2012 on a study of the apo-E-boosting drug, bexarotene. Already FDA-approved for use against a rare skin cancer, bexarotene showed a strong ability to remove amyloid beta from the brains of mice that overproduce the protein. The treatment also improved the animals’ memory. “We’re now just about to start a pilot trial of the drug in a small group of human subjects,” says Landreth. The trial is meant to confirm that in humans, as in mice, bexarotene increases the rate of apo-E synthesis in the brain along with the rate of amyloid beta clearance. If this initial trial is successful, further tests of bexarotene as a treatment or preventive of Alzheimer’s could follow.
Lysosomes and Autophagy
Other research groups are concentrating on a different and more general aggregate-disposal mechanism in the brain, known broadly as lysosomal disposal. Lysosomes are acid- and enzyme-filled sacs within cells that essentially eat and recycle waste matter, including protein aggregates. This lysosomal eating process, when it gobbles a cell’s internal waste, is called “autophagy.” Neurons appear to rely heavily on lysosomes and autophagy because of their extended lifetimes, but this powerful cellular housekeeping system is increasingly overburdened as our brains age. “All the cellular disrepair that comes with aging, all the damaged proteins and other structures—all that has to be removed by autophagy,” says Ralph A. Nixon, M.D., Ph.D., a professor of psychiatry and cell biology at New York University’s Langone Medical Center.
In C. elegans experiments, boosting autophagy appears to be a major pathway through which reduced insulin signaling increases protein waste-handling capacity and lifespan. Conversely, in mice, knocking out key components of the autophagy system causes an accumulation of aggregates and neurodegeneration. As Nixon’s and other investigators’ work suggests, autophagy-related processes are apt to be both overburdened and disrupted in Alzheimer’s, Parkinson’s, and other neurodegenerative diseases—and boosting autophagy has been shown to ameliorate standard mouse models of these diseases.
A number of labs, including Nixon’s and Finkbeiner’s, are now trying to develop autophagy boosters for potential human use. Finkbeiner, in partnership with a major pharma company, is developing autophagy-enhancing drugs that are chemically based on existing, FDA-approved drugs. He and his colleagues have had particularly promising results already in a mouse model of ALS, in which their drug shortens the half-life—by speeding the clearance—of TDP-43 in affected cells. “We not only have demonstrated a beneficial effect on survival, but also have made progress on understanding the mechanism of action,” he says.
The other major waste-disposal mechanism within neurons is the proteasome, a large, roving structure that acts as a protein-cutting enzyme. It targets malformed or aggregated proteins that have been tagged with ubiquitin molecules. This system grows less efficient with age , appears to be impaired somehow in Alzheimer’s , and is often markedly weakened in Parkinson’s patients . As with autophagy, researchers now are seeking to boost proteasomal waste-disposal as a means to prevent or slow neurodegeneration. In 2010, for example, researchers at Harvard Medical School reported in Nature that they had discovered a basic regulator of proteasomal activity, an enzyme called USP14 that removes the ubiquitin “dispose this” tags from malformed proteins. Their biotech company, Proteostasis Therapeutics, is now developing at least one drug that can inhibit USP14 in the brain, thus boosting proteasomal efficiency.
There are still some caveats. Enhancing proteasomal or autophagic activity in a person’s cells might increase an incipient tumor’s ability to survive; indeed, proteasomal inhibitors now represent a distinct class of anti-cancer drugs. There are also some forms of neurodegeneration that might get worse, not better, if waste-protein disposal systems are boosted. One reason would be that the disposal systems are already dysfunctional, so that making them work harder is counterproductive. Another would be that, in rare cases, the enhanced protein-removal rate excessively depletes good proteins—one such case was reported last summer by the laboratory of biologist Thomas Südhof, M.D., at Stanford University. That result, in mice with a genetic neurodegenerative condition, “suggests that one shouldn’t just assume that proteasomal activation will always be beneficial,” says Südhof, a member of the Dana Alliance for Brain Initiatives.
For the time being, the notion of boosting these disposal systems for therapeutic effect will certainly be evaluated on a disease-by-disease basis. “It may also be that intervention is limited to a specific disease stage in each case,” says Finkbeiner. “But I still feel pretty optimistic. This [protein waste disposal] is a normal process. You activate it when you fast, and that seems to be good for you.”
Could a pill designed to have the same mild effect end up being taken even by healthy older adults, to keep their brains clear—much as statins now keep their arteries clear?
“That’s a pretty good analogy,” Finkbeiner says.
Published November 2012
 “Neocortical neurogenesis in humans is restricted to development,” by R.D. Bhardwaj et al, Proceedings of the National Academy of Sciences 2006 (vol. 103, August 15): 12564-8.
 “A mutation in APP protects against Alzheimer's disease and age-related cognitive decline,” by T. Jonsson et al, Nature (vol. 488, August 2): 96-9.
 “Lifespan brain activity, β-amyloid, and Alzheimer's disease,” by W.J. Jagust and E.C. Mormino, Trends Cogn Sci. 2011 (vol. 15, November): 520-6.
 “Decreased clearance of CNS beta-amyloid in Alzheimer's disease,” K.G. Mawuenyega et al, Science 2010 (vol. 330, Dec 24): 1774.
 “Regulation of aging and age-related disease by DAF-16 and heat-shock factor,” A.L. Hsu et al, Science. 2003 (vol. 300, May 16): 1142-5.
 “Reduced IGF-1 signaling delays age-associated proteotoxicity in mice,” E. Cohen et al. Cell. 2009 (vol. 139, Dec 11): 1157-69.
 “Human apoE isoforms differentially regulate brain amyloid-β peptide clearance,” J.M. Castellano et al, Sci Transl Med. 2011 (vol. 3, Jun 29): 89ra57.
 “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models,” P.E. Cramer et al., Science 2012 (vol. 335, Mar 23): 1503-6.
 “Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice,” by T. Hara et al, Nature. 2006 (vol. 441, Jun 15): 885-9.
 “Autophagy and neuronal cell death in neurological disorders,” R.A. Nixon and D.S. Yang, Cold Spring Harb Perspect Biol. 2012 (vol. 4, Oct 1).
 “Changes of the proteasomal system during the aging process,” M.A.Baraibar and B. Friguet, Prog Mol Biol Transl Sci 2012 (vol. 109): 249-75.
 “The Ubiquitin-Proteasome System and the Autophagic-Lysosomal System in Alzheimer Disease,” Y. Ihara et al, Cold Spring Harb Perspect Med. 2012 (vol. 2, Aug 1).
 “Gene expression profiling in human neurodegenerative disease,” J. Cooper-Knock et al, Nat Rev Neurol. 2012 (vol. 8, Sept): 518-30.
 “Enhancement of proteasome activity by a small-molecule inhibitor of USP14,” B-H Lee et al, Nature 2010 (vol. 467, Sept 9): 179–184.
 “Proteasome inhibition, the pursuit of new cancer therapeutics, and the adaptor molecule p130Cas,” D. Chauhan and K.C. Anderson, BMC Biology 2011 (vol. 9): 72.
 “Proteasome inhibition alleviates SNARE-dependent neurodegeneration,” M. Sharma et al, Sci Transl Med. 2012 (vol. 4, Aug 15): 147ra113.