Why Should We End Aging Forever? If you had to choose right now, how long would you want to live? 80 years? 90? 120? Longer? And do you think you'll change your mind once you reach that age? Fifty thousand years ago most humans died very young. As we learned how to use the resources around us to treat ourselves, this got better and better. Today, humans are living longer and healthier lives than ever before. But this has an unforeseen consequence. We spend an ever-increasing part of our lives being sick and in need of care. Most of us will die in a hospital bed, which is depressing enough by itself. But we also have to witness the same happening to our loved ones. Except, maybe we can stop this forever. The most effective way to treat a disease is to prevent it as we know the provoke prevention is better than cure. It saves many more lives if you stop a million people from smoking, than coming up with better chemotherapies. So why not put a halt to the cause of all disease: the process of aging. In a nutshell, aging is caused by physics, and not biology. Think of cars. Parts wear down from rubbing and grinding. Metal rusts. Filters get plugged. Rubber cracks. Our bodies are worn down by trillions of tiny physical processes; Oxygen, radiation from the sun, our metabolism. Our bodies have many mechanisms to repair this damage, but over time they become less effective. So our bones and muscles weaken. Our skin wrinkles. Our immune system gets weaker. We lose our memory and our senses diminish. There's no such thing as dying of old age. We all die because one of our important parts breaks. The older we get, the more damaged and fragile we become until one or multiple diseases take over and kill us. Unnoticed by most of us, longevity research has made some unprecedented advances in the last few years. For the first time, we're starting to understand the mechanisms behind aging and how to manipulate them. Aging is neither mystical nor inevitable, and we might be able to stop or delay it during your lifetime. But first, if we could, should we end aging? Is this a good idea? The end of aging or life extension makes many people uncomfortable. We're born, are young, become older, and then we die. This has been the natural order for literally all of human history, and getting old is a good thing, right? We celebrate the idea of living long enough to experience old age. We even call them the golden years. But the reality is that everybody wants to become old, but nobody wants to be old. Thousands of years ago, humans already feared neverending old age. But ending aging does not mean getting weaker and weaker. If you become too old, it's too late. A 90 year old who stopped aging would die anyway after a few years. Too much damage has been done to his internal machinery. There are already too many surfaces for disease to attack. Instead, the concept of life extension promises to end diseases, and with them, the end of a fixed maximum age. We don't know how much we could prolong our lives. We might make every human healthy to the currently accepted maximum age of around 120, or we might stop biological aging and disease indefinitely. Nobody knows at this point what's possible. Okay, but even if we could achieve that, should we? Well, life extension is really just another phrase for medicine. All the doctors are doing is trying to prolong life, and minimize suffering. The vast majority of healthcare resources are spent on the consequences of aging. Nearly half of your lifetime healthcare costs will be spent during your senior years, and another third during middle age. We are actually already trying to prolong life with our current medicine. We're just doing it very inefficiently. Trying to stop aging from happening is not less natural than transplanting a heart, treating cancer with chemotherapy, using antibiotics or vaccines. Nothing humans do nowadays is purely natural anymore, and we enjoy the highest standard of living ever as a consequence of that. What we're doing right now is waiting until it's too late and the machine is failing. And then we use the vast majority of our resources trying to fix it as well as we can, while it breaks down even further. But life extension still feels hubristic. Most people assume that they will want to die once they reach a certain age, and this might still be true. The idea of avoiding death entirely is off-putting for many. The end of biological aging would not be in the end of death in any way. It's more like a summer evening when you were a kid, and your mom called you inside. You just wanted to keep playing, have a little more fun during sunset before you went to sleep. It's not about playing outside forever, just a little longer, until we feel tired. If you imagine a world without disease where you and your loved ones could live in good health for another 100 or 200 years, how would this change us? Would we take better care of our planet if we knew we would be around longer? If we could work for 150 years, how much time would we spend figuring out what we're good at? How much more time would we spend learning? Would the intense feeling of pressure and stress many of us are feeling right now, go away or get worse? So asking again, if you could choose how long to live right now, in good health and with your friends and family, what's your personal answer? What would you like your future to look like? But maybe you're still unconvinced. Some nagging feeling remains. That is the Reaper whispering into your brain. Why we age? While many search for the proverbial fountain of youth, you might be wondering why do we age in the first place? What is it about our bodies or cells biologically that causes us to grow old? There is a variety of internal and external factors such as diet, exercise or environmental stress which all contribute to cell damage and repair and effect the rate of aging, But the surprising truth is that apart from these, we actually have a biological clock buried within our genetic makeup. And this clock can only run for so long, in other words we are programmed to die. Your body is made up of trillions of cells which are constantly going through cell division and every time they divide they make a copy of their DNA as well. This DNA is tightly packed into structures called chromosomes of which humans have twenty three pairs. The problem is, DNA replication isn't quite perfect and skips over the end of each chromosome. To protect against important DNA information being cut out we have something called telomeres on the end of chromosomes which are essentially meaningless repeats of DNA that we can afford to lose. But every time our cells divide these telomeres become shorter and shorter until eventually they've been entirely stripped away. At which point the cell no longer divides. Some flat worms are able to endlessly regenerate their telomeres making them effectively biologically immortal, but their lifespans do vary and they're still susceptible to disease further suggesting that aging is a mix of genetic and environmental factors. But why don't our cells do this? Ultimately this replication limit actually helps to prevent cancer which is the uncontrollable growth of cells and evasion of cell death. The point at which a cell stops replicating is known as cellular senescence. In humans this replication limit is around fifty times. Once it is reached the cell gradually begins to lose its function and die causing age-related characteristics. This also helps to explain why life expectancy is a strongly heritable trait from your parents, because you got your initial telomere length from them. 4. Mitochondrial DNA 'Spring Cleaning' Could Prevent Aging Researchers from Caltech and UCLA have developed a new approach to removing cellular damage that accumulates with age. The technique can potentially help slow or reverse an important cause of aging. Led by Nikolay Kandul, senior postdoctoral scholar in biology and biological engineering in the laboratory of Professor of Biology Bruce Hay, the team developed a technique to remove mutated DNA from mitochondria, the small organelles that produce most of the chemical energy within a cell. A paper describing the research appears in the November 14 issue of Nature Communications. There are hundreds to thousands of mitochondria per cell, each of which carries its own small circular DNA genome, called mtDNA, the products of which are required for energy production, which makes the mere presence of a detected mutation more difficult to functionally interpret Because mtDNA has limited repair abilities, normal and mutant versions of mtDNA are often found in the same cell, a condition known as heteroplasmy The accumulation of mutant mtDNA over a lifetime is thought to contribute to aging and degenerative diseases of aging such as Alzheimer's, Parkinson's, and sarcopenia—age-related muscle loss and frailty "We know that increased rates of mtDNA mutation cause premature aging," says Hay, Caltech professor of biology and biological engineering. "This, coupled with the fact that mutant mtDNA accumulates in key tissues such as neurons and muscle that lose function as we age, suggests that if we could reduce the amount of mutant mtDNA, we could slow or reverse important aspects of aging." The team—in collaboration with Ming Guo, the P. Gene and Elaine Smith Chair in Alzheimer's Disease Research and professor of neurology and pharmacology at UCLA, and UCLA graduate student Ting Zhang—genetically engineered Drosophila, the common fruit fly, so that about 75 percent of the mtDNA in muscles required for flight, one of the most energy demanding tissues in the animal kingdom, underwent mutation in early adulthood. This model recapitulates aging in young animals. Drosophila grow quickly and most human disease genes have counterparts in the fly, making it an important model in which to study human disease-related processes. The researchers chose to focus on muscle because this tissue undergoes age-dependent decline in all animals, including humans, and it is easy to see the consequences of loss of function. However, cells can break down and remove dysfunctional mitochondria through a process called mitophagy, a form of cellular quality control. What was unclear prior to this work was whether this process could also promote the selective elimination of mutant mtDNA. The team found that when they artificially increased the activity of genes that promote mitophagy, including that of several genes implicated in familial forms of Parkinson's disease, the fraction of mutated mtDNA in the fly muscle cells was dramatically reduced. For example, overexpressing the gene parkin, which is known to specifically promote the removal of dysfunctional mitochondria and is mutated in familial forms of Parkinson's disease, reduced the fraction of mutant mtDNA from 76 percent to 5 percent, while the overexpression of the gene Atg1 reduced the fraction to 4 percent. "Such a decrease would completely eliminate any metabolic defects in these cells, essentially restoring them to a more youthful, energy-producing state," notes Hay. "The experiments serve as a clear demonstration that the level of mutant mtDNA can be reduced in cells by gently tweaking normal cellular processes." "Now that we know mtDNA quality control exists and can be enhanced, our goal is to work with Dr. Guo's lab to search for drugs that can achieve the same effects," Hay adds. "Our goal is to create a future in which we can periodically undergo a cellular housecleaning to remove damaged mtDNA from the brain, muscle, and other tissues. This will help us maintain our intellectual abilities, mobility, and support healthy aging more generally." Role of mitochondria in aging regulates the innate immune system Mitochondrial DNA is the small circular chromosome found inside mitochondria. The mitochondria are organelles found in cells that are the sites of energy production. the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging. While prokaryotes can be viewed as immortal, their seemingly more advanced cousins, eukaryotes, all are cloaked in a more complex but mortal shell. What regulates this mortality and controls why humans age is undoubtedly multifactorial. Here, however, we focus on one appealing cause of aging that can be traced back to an unwitnessed event that occurred over 1.5 billion years ago. The event in question involved the entry of an immortal prokaryote into a eukaryote cell. This beneficial union, or symbiogenesis, would eventually lead the invading prokaryote to evolve into what we now more commonly call the mitochondria. The notion that the seed of our mortality can somehow be linked to this unlikely billion-year-plus marriage has been appreciated for quite some time. In the 1920s, Raymond Pearl noted that metabolic rates appeared to inversely correlate with lifespan. Building on this, Denham Harman, in the 1950s, proposed the free radical theory of aging. Harman’s conjecture was that the generation of reactive oxygen species (ROS), which he viewed as likely coming from the mitochondria, gave rise to the subsequent accumulation of damaged proteins, lipids, and DNA, thereby fueling aging and age-related diseases in an inevitable but stochastic process. While the notion that increased mitochondrial ROS directly causes aging has fallen into disfavor, in its wake, other aspects of mitochondrial biology have grown increasingly more appealing. Some links between aspects of mitochondrial biology and aging have been the subject of many excellent recent reviews Here, we focus on those aspects of mitochondrial physiology that have perhaps the strongest connection to human aging. These processes include the emerging role that mitochondria play in inflammation; how dysregulation of mitochondrial quality control and age-related mitochondrial dysfunction contributes to aging, age-related mitochondrial dysfunction, and the notion of retrograde signaling; and why a little mitochondrial stress might ultimately be a good thing. Interestingly, a number of preclinical observations suggest that the activation of the inflammasome may be maladaptive. For instance, in mice, genetic deletion of NLRP3 appears to reduce the inflammation associated with aging and slow the age-dependent incidence of insulin resistance, cognitive decline, and frailty In this trial, over 10,000 patients who had suffered a previous myocardial infarction were randomized to placebo or one of three doses of canakinumab. Interestingly, this antiinflammatory strategy appeared to reduce subsequent cardiovascular events. Secondary analysis moreover suggested that the development of fatal lung cancers might also be reduced There is increasing evidence that mitochondria might play an important role in the inflammaging phenotype. The immune system is capable of sensing and responding to tissue damage and views the release of intracellular molecules in an analogous fashion to dangerous pathogens. This “danger theory” argues that certain molecules released from senescent or dying cells might constitute signals that trigger an immune response, often termed damage-associated molecular patterns (DAMPs). Interestingly, circulating mtDNA appears to increase gradually with age after the fifth decade of life Unlike mutations in the DNA in the nucleus, which can be corrected through cellular repair mechanisms, mutations in mtDNA are often not repaired. While mtDNA encodes critical proteins required for electron transport, it is generally believed that any pathogenic mtDNA mutation would need to reach a threshold of more than 60% and perhaps closer to 90% in a given cell or tissue to have a measurable bioenergetic effect. Most likely, the increase in mtDNA mutational load is a correlate of aging rather than being primarily responsible for the aging phenotype.When a critical threshold level of mutant mtDNA is passed, cells become nonfunctional or die. . Inherited defects in mtDNA are also linked to a number of conditions found in children, including autism. . Most people start off life with some level of heteroplasmy, and the levels of mutant mtDNA increase throughout life, which are inherited from mother to child, are readily apparent in almost everyone. Levels of mitochondrial mutations certainly increase with age. Yet the abundance of mitochondrial genomes, ranging from hundreds to thousands of copies per cell, makes the mere presence of a detected mutation more difficult to functionally interpret. Indeed, next-generation sequencing methods have determined that a low level of mutant mitochondrial genomes (termed heteroplasmy), which are inherited from mother to child, are readily apparent in almost everyone. Yet the functional implications of these sequencing results are less clear. While mtDNA encodes critical proteins required for electron transport, it is generally believed that any pathogenic mtDNA mutation would need to reach a threshold of more than 60% and perhaps closer to 90% in a given cell or tissue to have a measurable bioenergetic effect. Most likely, the increase in mtDNA mutational load is a correlate of aging rather than being primarily responsible for the aging phenotype. Nonetheless, experimental evidence suggests that the germline load of mtDNA mutations can shape the subsequent rate of aging. Moreover, there are engineered mouse models, such as the proofreading-deficient, mtDNA polymerase (POLγ) mouse, that do accumulate extremely high levels of mitochondrial mutations. Notably, these animals also exhibit a shortened lifespan, along with certain visible age-related phenotypes including gray hair and kyphosis. Thus, mtDNA mutations can, at high levels, drive mammalian aging. This is also evident in human subjects who carry mutations in the mitochondrial replication machinery. Indeed, over 300 pathological mutations exist in human POLγ, and these mutations are linked to the development of a wide spectrum of conditions, including Parkinson’s disease and other age-related pathologies. Another potentially more common example is the growing realization that patients with chronic HIV infection exhibit aspects of accelerated aging, including increased frailty, augmented cardiovascular disease, and significantly higher rates of bone fractures. While these conditions might be secondary to the chronic low-level inflammation associated with viral infection, it is of interest to note that certain HIV therapeutics have known off-target effects, including an ability to inhibit POLγ activity. This raises the possibility that this growing clinical syndrome might phenocopy aspects of the proofreading-deficient POLγ mouse. Indeed, HIV-positive patients treated with nucleoside analog drugs have increased levels of mitochondrial mutations that correlate with the duration of antiretroviral therapy mtDNA can be present in hundreds to exist with wild-type mtDNA in a condition called heteroplasmy. Many of these heteroplasmic mutations have been correlated with and aging and age-associated diseases. mtDNA mutations and deletions have been identified as drivers of a range of Parkinson’s disease Alzheimer’s disease, cancer, sarcopenia, heart disease and diabetes. Maternal age can affect transmission of mtDNA heteroplasmicities Until recently, the study of mtDNA damage had been challenging due to the difficulty of detecting variations present in low abundance in any particular cell or tissue. In contrast to nuclear DNA, which is present in only two copies per cell, mtDNA can be present in hundreds to thousands of copies, and these do not always contain the same sequence. Mutated mtDNA can coexist with wild- type mtDNA in a condition called heteroplasmy. The development of next generation sequencing or ultra-deep sequencing has helped to characterize both mtDNA heteroplasmicity and the different types of damage and mutations that can be present in disease and aging. Some recent studies have suggested that heteroplasmy may serve a protective role since the ratio of mutant to wild-type DNA is key to the development of disease. This ratio is the determinant of the so called “Threshold Effect”; pathogenic mutations need to reach at least 70 to 90% of heteroplasmy to have a detrimental effect on mitochondrial function. This threshold effect has been mimicked in a Drosophila model by manipulating a mitochondrial ribosomal gene, achieving different pathological phenotypic manifestations depending on the mutation dosage. Therefore it is suggested that for mtDNA damage to produce detrimental effects, the mutation levels must reach high frequency within each cell, a process that would take many years to occur. To examine this process in human aging, Christiansen and colleagues along with Lee and colleagues found declines in mtDNA copy number in whole blood to occur with age and lower mtDNA copy number to be associated with poorer health outcomes. This work was followed up Gu and colleagues who used available whole-genome sequencing data from peripheral blood mononuclear cells from more than 1500 women from two British cohorts. They found that aged individuals accumulated higher levels of mutant mtDNA than younger women and that these were associated with the appearance of age-related blood physiological markers. A very recent study has found a positive correlation in elderly subjects between the abundance of the pathological A3243G mtDNA mutation and reduced strength, cognition, metabolism and cardiovascular fitness. They also reported that the patients with the highest mutation burden presented a higher risk of dementia and stroke mortality. A high frequency of mtDNA deletions in the D-Loop has also been observed in the central nervous system of 27-month-old rats and mice when compared to 7-month-old animals.The D-Loop is the region of mtDNA most prone to genome instability. This is likely because it is the most exposed region as the primary replication initiation site. Studies have shown, D-loop has high levels of DNA point mutations with age in a range of tissues including the brain, blood, skin, muscle and heart. One of the most common mutations is a T414G transversion which has been found in up to 50% of mtDNA molecules of half of the individuals tested above 65 years of age. Large mtDNA deletions have also been detected in human mtDNA during aging. A 5 kb deletion of mtDNA, which is usually associated with mitochondrial disease, has been reported to accumulate in the heart, brain and muscle of aging humans. There is evidence that mtDNA defects can clonally expand and create mosaic phenotypes in some tissues. Ragged red fibers (RRF) are muscles fibers with mitochondria deficient for cytochrome c oxidase (respiratory complex IV) activity, that can result from mutations or deletions in either mtDNA or nDNA. These fibers accumulate with age and are thought to be a contributing factor for sarcopenia. Further supporting the role of clonal expansion, Khrapko and colleagues found clonal mutant mtDNA that had expanded from an initial single mtDNA molecule in human buccal epithelium and cardiac muscle. Similarly, Turnbull and colleagues reported a clonal expansion of mtDNA mutations in the colorectal epithelium with age, while the frequency of de novo mtDNA mutations did not increase, suggesting that clonal expansion is the driving force behind mitochondrial dysfunction with age. Similar clonal expansion events have been observed in skin fibroblasts and blood of elderly subjects, producing an elevated load of heteroplasmic or even homoplasmic mutations. In some cases, it is thought that the origin of clonal expansion could arise from stem-cell aging. It was shown within normal gastric epithelium that mtDNA mutations are present in its stem-cells which are then passed on to the differentiated progeny