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
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regulates the innate immune system
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Mitochondrial DNA is the small circular chromosome found inside mitochondria. The
mitochondria are organelles found in cells that are the sites of energy production.
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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
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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