Project: Lipofuscin-Destroying Enzymes to Treat Macular Degeneration
Lysosomes are the cell’s waste incinerators, responsible for destroying all kinds of molecules when they are no longer needed. Thus, they harbor an impressive array of enzymes capable of attacking and breaking many substances, but not all. Some molecules are formed so slowly that evolution “did not select for” an enzyme for degrading them. Rather, these molecules are stored in the lysosomes, and accumulate over the entire life span until they get in the way of the affected cells’ normal functioning and cause disease. Medical bioremediation is the proposal to destroy these molecules using lysosomal enzyme therapy. See De Grey AD, Alvarez PJ, Brady RO, Cuervo AM, Jerome WG, McCarty PL, Nixon RA, Rittmann BE, Sparrow JR. Medical bioremediation: prospects for the application of microbial catabolic diversity to aging and several major age-related diseases. Ageing Res Rev. 2005 Aug;4(3):315-38. PMID 16040282.
Dr Cuervo is one of the researchers featured in the NY Times article.
LysoSENS
Destroying junk inside cells is one of the seven targets of SENS
Trends in Cell Biology article : The regulation of aging: does autophagy underlie longevity? is the primary basis of the NY Times article The Trends in Cell Biology article is by Tibor Vellai , Krisztina Takács-Vellai1, Miklós Sass and Daniel J. Klionsky.
The accumulation of cellular damage is a feature common to all aging cells and leads to decreased ability of the organism to survive. The overall rate at which damage accumulates is influenced by conserved metabolic factors (longevity pathways and regulatory proteins) that control lifespan through adjusting mechanisms for maintenance and repair. Autophagy, the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles, is implicated in aging and in the incidence of diverse age-related pathologies. Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species
Our cells build two kinds of recycling factories. One kind, known as the proteasome, is a tiny cluster of proteins. It slurps up individual proteins like a child sucking a piece of spaghetti. Once inside the proteasome, the protein is chopped up into its building blocks.
For bigger demolition jobs, our cells rely on a bigger factory: a giant bubble packed with toxic enzymes, known as a lysosome. Lysosomes can destroy big structures, like mitochondria, the sausage-shaped sacs in cells that generate fuel. To devour a mitochondrion, a cell first swaddles it in a shroudlike membrane, which is then transported to a lysosome. The shroud merges seamlessly into the lysosome, which then rips the mitochondrion apart. Its remains are spit back out through channels on the lysosome’s surface.
Lysosomes are versatile garbage disposals. In addition to taking in shrouded material, they can also pull in individual proteins through special portals on their surface. Lysosomes can even extend a mouthlike projection from their membrane and chew off pieces of a cell.
The shredded debris that streams out of the lysosomes is not useless waste. A cell uses the material to build new molecules, gradually recreating itself from old parts. “Every three days, you basically have a new heart,” said Dr. Ana Maria Cuervo, a molecular biologist at Albert Einstein College of Medicine.
This self-destruction may seem like a reckless waste of time and energy. Yet it is essential for our survival, and in many different ways. Proteasomes destroy certain proteins quickly, allowing them to survive for only about half an hour. That speed allows cells to keep tight control over the concentrations of the proteins. By tweaking the rate of destruction, it can swiftly raise or lower the number of any kind of protein.
Lysosomes, which eat more slowly than proteasomes, serve different roles that are no less essential. They allow cells to continue to build new molecules even when they are not getting a steady supply of raw ingredients from the food we eat. Lysosomes also devour oily droplets and stores of starch, releasing energy that cells can use to power the construction of new molecules.
The decline of autophagy may be an important factor in the rise of cancer, Alzheimer’s disease and other disorders that become common in old age. Unable to clear away the cellular garbage, our bodies start to fail.
Dr. Cuervo and her colleagues, for example, have observed that in the livers of old mice, lysosomes produce fewer portals on their surface for taking in defective proteins. So they engineered mice to produce lysosomes with more portals. They found that the altered lysosomes of the old experimental mice could clear away more defective proteins. This change allowed the livers to work better.
“These mice were like 80-year-old people, but their livers were functioning as if they were 20,” Dr. Cuervo said. “We were very happy about that.”
Andrea Ballabio, the scientific director of Telethon Institute of Genetics and Medicine in Naples, Italy, and his colleagues have found another way to raise autophagy. By studying the activity of genes that build lysosomes, they discovered that at least 68 of the genes are switched on by a single master protein, known as TFEB.
When Dr. Ballabio and his colleagues engineered cells to make extra TFEB, the cells made more lysosomes. And each of those lysosomes became more efficient. The scientists injected the cells with huntingtin, a protein that clumps to cause the fatal brain disorder Huntington’s disease. The cells did a much better job of destroying the huntingtin than normal cells.
Brian Wang is a Futurist Thought Leader and a popular Science blogger with 1 million readers per month. His blog Nextbigfuture.com is ranked #1 Science News Blog. It covers many disruptive technology and trends including Space, Robotics, Artificial Intelligence, Medicine, Anti-aging Biotechnology, and Nanotechnology.
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