Fight Aging!

Researchers have recently mapped a specific mechanism by which autophagy is connected with the onset of cellular senescence. Both autophagy and cellular senescence are important topics in aging research, associated with aging and longevity.

Autophagy is a set of complex recycling processes used by cells to eliminate damaged components and some forms of unwanted waste. In its most familiar form, autophagy involves tagging a cellular component such as a damaged mitochondrion, wrapping it in a membrane, and transporting it to a lysosome where it is dismantled. Enhanced autophagy has been observed in many of the methods and interventions shown to modestly slow aging in animal studies, though as is the case for calorie restriction it is very hard to pick out the degree to which any one change is responsible for slowing the pace of aging. Everything in the operation of cellular metabolism is interconnected, it is an enormously complex set of feedback loops and relationships, and nothing can be altered in isolation. That said, some studies in which researchers deliberately set out to increase the level of autophagy have shown life extension in lower animals, and it is not unreasonable to believe that increased cellular housekeeping should result in slower aging. Some researchers believe that autophagy is the important mechanism in most methods of slowing aging demonstrated to date. There is some interest in the research community in producing treatments based on enhancement of autophagy, but as yet there has been little concrete movement in this direction beyond early-stage investigations.

Cellular senescence is an evolved response to stresses, toxicity, and damage in tissues that, among other things, serves to reduce the risk of cancer by removing cells from the cycle of replication. A senescent cell ceases to divide and secretes signals that encourage nearby cells to also become senescent. Unfortunately this only works when comparatively few senescent cells exist. Once many of them accumulate, as happens by the time later life rolls around, their presence produces a range of very harmful effects on organs and tissues, and they even corrupt the local environment to the point of encouraging cancer growth. Senescent cells are removed by the immune system to some degree, but this also fails with aging. One of the most promising near-future rejuvenation therapies involves clearance of senescent cells, which might be achieved via any form of targeted cell destruction technology that can clearly identify the characteristic senescent cell chemistry from that of a normal cell. A proof of concept in mice showing improved health as a result of clearance was published earlier this year, and separately Oisin Biotechnology was seed funded to develop another method of clearance applicable to humans. A clearance method that reduces senescent cell levels to those present in a 30-something adult can be repeated as needed and can in principle completely remove this contribution to the aging process.

Given all this it is interesting to see one of the modes of autophagy and initiation of cellular senescence linked as described below, though the researchers' ideas for turning their work into potential treatments sound a lot more complicated and less likely to succeed than the easier target of simply destroying senescent cells every so often. One of the great advantages of senescent cell clearance as an approach is that it sidesteps an awful lot of work; figuring out exactly how and why senescent cells are produced and cause harm becomes an optional nice-to-have if you can just get rid of them.

Autophagy Works in Cell Nucleus to Guard Against Start of Cancer

The material that autophagy can digest ranges from a single molecule to a whole bacterium. Previously, all known substances consumed by autophagy took place outside the nucleus in the cell's cytoplasm. In the new study autophagy is shown, for the first time, to digest nuclear material in mammalian cells. "We found that the molecular machinery of autophagy guides the degradation of components of the nuclear lamina in mammals." The nuclear lamina is a network of protein filaments lining the inside of the membrane of the nucleus. It is a crucial network in the nucleus, providing mechanical support to the nucleus and also regulating gene expression by making some areas of the genome less or more available to be transcribed into messenger RNA.

In response to cellular stress that can cause cancer, the team found that LC3, chromatin, and laminB1 migrate from the nucleus - via nuclear blebs - into the cytoplasm and are eventually targeted for disposal. This breakdown of laminB1 and other nuclear material leads to a cellular state called senescence. Human cells have complicated ways to protect themselves from becoming cancerous, and one way is to drive themselves to become senescent, so that the cells can no longer replicate.

The team showed that when a cell's DNA is damaged or an oncogene is activated (both of which can cause cancer), a normal cell triggers the digestion of nuclear lamina by autophagy, which promotes senescence. Inhibiting this digestion of nuclear material weakens the senescence program and leads to cancerous growth of cells. "The nucleus is the headquarters of a cell. When a cell receives a danger alarm, amazingly, it deliberately messes up its headquarters, with the consequence that many functions are completely stopped for the cell. Our study suggests this new function of autophagy as a guarding mechanism that protects cells from becoming cancerous."

Although senescence suppresses cancer, which is the good side of this physiological balance, there is also a dark side. Senescence is associated with normal aging, and senescent cells accumulate in aged tissues, which impair the normal functions of the tissue and contribute to age-related diseases. The team noted that while autophagy digestion of the nucleus is able to restrain cancer, this machinery is improperly turned on during normal aging. "There is a short term 'tactical' advantage, but a long term 'strategic' defeat. This mechanism makes a normal cell, even without cancer stress, get old much faster, and in a detrimental way."

In support of this notion, the team found that in late middle-aged normal cells, blocking the autophagy-driven breakdown of the nuclear lamina can make cells live 60 percent longer. Looking toward the future, the team reasons that specific manipulation of the nuclear digestion by autophagy holds promise to intervene in age-related diseases. The team showed that a blocking peptide, which inhibits LC3-laminB1 interaction, is able to slow cell aging. The implications are that a small molecule could be made to stop the long-term dark side of the senescence pathway, and to treat age-related diseases, especially those related to chronic inflammation as seen in human aging.

Autophagy mediates degradation of nuclear lamina

Macroautophagy (hereafter referred to as autophagy) is a catabolic membrane trafficking process that degrades a variety of cellular constituents and is associated with human diseases. Although extensive studies have focused on autophagic turnover of cytoplasmic materials, little is known about the role of autophagy in degrading nuclear components. Here we report that the autophagy machinery mediates degradation of nuclear lamina components in mammals. The autophagy protein LC3/Atg8, which is involved in autophagy membrane trafficking and substrate delivery, is present in the nucleus and directly interacts with the nuclear lamina protein lamin B1, and binds to lamin-associated domains on chromatin. This LC3-lamin B1 interaction does not downregulate lamin B1 during starvation, but mediates its degradation upon oncogenic insults, such as by activated RAS. Lamin B1 degradation is achieved by nucleus-to-cytoplasm transport that delivers lamin B1 to the lysosome. Inhibiting autophagy or the LC3-lamin B1 interaction prevents activated RAS-induced lamin B1 loss and attenuates oncogene-induced senescence in primary human cells. Our study suggests that this new function of autophagy acts as a guarding mechanism protecting cells from tumorigenesis.