The Curse of Aging, Part 1: Definition and History

Aging research, something which has steadily been developing for several decades, has recently reached critical mass to begin establishing itself as a cultural phenomenon.  At the same time, it remains one of the most misunderstood subjects I can think of.  Over the past 2 or 3 years I have seen front page headlines on Discover magazine, Time, even The Economist about modern aging science, though article quality ranges from totally uneducated to decently good.  Ambition has grown beyond the walls of academia and into Silicon Valley, though still infrequently into doctors offices.  A thriving online community has formed with multiple subdivisions, but I have met only a few people on the street with any affiliation to the community.

Today my entry will be the first of a 3 part series about modern aging science, with the aim of bringing understanding to non scientists.  As a PhD student with several years of past research experience related to aging, and a long standing interest in this subject, I’m excited to write about it.

  • The first part will be about the definition of the term “aging” and a brief overview of the philosophy, ethics and economics of it (some of the most mistreated subjects in the news coverage) followed by an overview of the history of aging research.  History is important in this context in the same way learning about Galileo and Newton is essential for understanding astronomy: otherwise you are left with no context for discoveries and little ability to recognize what matters in the field.
  • The second will be 50% attributed to physiological aging and pathologies, a well understood subject in medicine representing the symptoms we actually see on the surface.  The other half will focus on molecular aging and modern theories of causative mechanisms, which are the building blocks of physiological aging as well as the basis for any treatment.
  • The third and last section will be the juicy part you all want to hear, but is quite useless without the first two.  That’s right, treatments and (hopefully) cures.  Spoiler: there is no one pill that will ever cure aging.  Combinations of lifestyle choices, protective compounds/foods, and biological therapies.

Aging Defined

For most of us who do not think of it consciously, aging is this:

age.jpg

One day we are young and pretty, the next day our hair is switched out for liver spots.  It’s a good start, as it shows that aging is something that tends to happen over time, i.e. biological age increases with chronological age.  My chronological age is 26, but my biological age on the surface is defined as fit and basically wrinkle free.

Of course, you may be thinking that this is all very cosmetic, and you’re right.  Biological aging is defined by a million more meaningful readouts than the state of one’s face at first glance.  Also, you may be thinking something like, “my grandma has wrinkles and she’s the most awesome person I know!  Aging is fine”.  But, let’s consider the end result of aging:

stone.jpg

And the last 5 years before that:

old

The death part invokes a mixed reaction in most of us, a mix of sadness and a level of inevitability we have established throughout our lives to come to a state of acceptance.  But, the sick guy is a reminder that aging can be torture, as most of us who have grandparents have seen.  Of course, it is possible to grow to accept being intubated in a hospital bed with no short term memory and few consistent acquaintances because you make everyone you love sad when they look at you.  But, on the same note I imagine people grow numb to waterboarding after awhile as well.

Okay, so the next argument which tends to arise is, “This is an age related disease, not aging itself”.  So, let’s get a little more well defined with all of this.

A good definition of age, according to Wikipedia, is this:

“In humans, ageing represents the accumulation of changes in a human being over time,[1] encompassing physical, psychological, and social change.”

Let’s stay focused on the physiology.  An accumulation of changes, those small biological alterations beneath the wrinkles, occurs over time.  Eventually, they add up to make someone less healthy and robust. That can cause suffering and death in two ways:

  1. Establishing a state of increased susceptibility to stochastic (randomly occurring) causes of death, such as cancer, heart attacks and pneumonia.
  2. Gradually moving an essential organ system to a state where it no longer functions, thus causing first suffering and then death.  Examples: Macular degeneration in the eye, Alzheimer’s in the brain.

More specific details on this in part 2, but just consider this:

disease.jpg

Despite the existence of childhood cancers, cancer rate goes from less than 1% in the 20’s to around 20% at 90.  Heart disease and arthritis show the same trend.  Asthma, on the other hand, is not an aging disease because it declines.  Diabetes show’s basically the same trend until 70, but then drops off because most people who have diabetes die young and thus are underrepresented (at the extremes of age this even happens with heart disease and dementia as well).  This doesn’t happen just randomly, it happens because deleterious biological changes accumulate and make people less robust and viable.

The one last thing to consider though, is the correlation with chronological aging (the passage of time).  How is it possible to do anything to improve aging, if all these issues inevitably accrue with time?

For the answer, imagine a 60 year old person with many moles on  their skin.  They receive a laser treatment and all the precancerous moles are killed, resulting in a huge reduction in skin cancer probability.  Is their biological age not reduced from one point to the next, as resistance to disease increases?  Or, what about an overweight pre-diabetic who begins an exercise program and improves their insulin sensitivity?

These and other treatments have existed for years, but the coming decades offer us promises to lead a revolution against these accumulating changes, and the inevitable hospital bed that follows.

Why Treat Aging?

The simple answer is that we have been for centuries.  Improvement in medicine have resulted in the average lifespan roughly doubling in industrialized countries over the past century.  But let’s look at three of the main arguments people use against taking action:

It’s not natural

Neither is aspirin.  Or, chemotherapy for that matter.  Or, thinking more broadly, you’re car, all the roads you drive on, or the house you live in.  Every technological and medical step forward is met with ideological resistance, which immediately breaks down for 90% of people when they see that they or their relatives suffer less.

In addition, as I’ll talk more about later, many short term treatments for aging are simply food or lifestyle changes that are probably more “natural” than their alternatives.

A Critical Step in Life is Accepting Death

This is very true, as a philosophical statement on it’s own.  The constant unease someone feels about their mortality is something that people have turned to spirituality and religion for for centuries.  People rock climb or ski so they can put themselves in a position where death is real enough to not be scary for a moment.  And, the death of others can inspire intense sadness which sparks a confrontation with our own emotional barriers and helps us reflect on the meaning of life.

However, people who are closer to death are not necessarily less afraid of it, or more willing to confront it.  The sunny view of old age as a time of inward reflection, where we see our grandkids playing outside and reflect on the beauty of the circle of life, represents a snapshot of time.  Indeed, 15 year olds may also have moments of incredible acceptance when reflecting on their eventual mortality.  The reality is that many people who are near the end are utterly terrified, synergistically enhanced by the physical and mental damage they have experienced already.

People often die with out having truly reached the last stage of grief, acceptance. And, perhaps most commonly, people simply choose to not consciously think about death until right as they’re dying.Don’t believe me? I speak from experience, but you can start by watching Extremis.

Aging enthusiasts tend to fall in a few categories.  There are those which care principally about healthspan, which means they don’t want to live any longer but they do want to live healthier for the duration and avoid getting sicknesses associated with age.  There are life-extensionists, those who want to extend the human lifespan because they feel that more life is more time to live, but not necessarily because they fear death.  They may want to live 150, 400, or 1 billion years, but the main idea is generally to enjoy more of the universe.  On the far end, a minority see anti aging research as a step towards eventual “true” immortality, something along the lines of Ray Kurzweill and the Singularity.  At least the first two are unlikely to be motivated by an unreasonable fear of death.  And, all anti-aging enthusiasts tend to confront death more directly than the average person anyways, which can be better for one’s psychology.

Overpopulation

Consider two populations of 100 people.  One grows at a rate of 1 child per couple for each 25 year generation, and everyone is immortal.  The other grows at a rate of 4 children per couple per generation, and people live 3 generations (75 years).

At 50 years, or 2 generations in, population 1 has 100+50+25 (generations 1,2, and 3), for a total of 175.  Population 2 has 100+200+400, or 700.  Already out to a big lead.

At 300 years, or 12 generations, population 1 has 100+50+25+12.5+6.25+3.2+1.6+0.8 +0.4+0.2+0.1+0.05, or about 200.  In fact, it has reached a theoretical limit at twice it’s original value.  Population 2, the short lived and baby loving population, has (100+200+400+800+1600+3200+6400+12800+25600+51200+102,400+204,800)-(all but the last 3 generations) = 358,400 people.  This tiny town has just become a medium sized city in 4 lifetimes.

 

The point is clear.  More babies makes the population balloon much faster than longer lifespan.  Only 1 baby may be a stretch, but in areas like Japan and parts of Europe it’s not off by much.  These places are already facing demographic problems from an increasing ratio of elderly to young people, which could itself be offset by rejuvenative therapies.

This last argument is one of several arguments about practicality and desirability, but you can get a more thorough discussion on these topics here.

History of Anti Aging Research

Realization of Mortality (unknown date) to Leonard Hayflick (1961).

Think back to the first time you realized that growing old means deteriorating and dying, and your conception of mortality was suddenly created.  Most likely your first thought was something like, “Oh shit, how do I avoid this?” before forgetting about it several minutes later.

I believe the pioneer of life extension research probably came a few million years ago, around when the first monkey simultaneously gained a conception of self, an ability to infer the future, and an obsessive complex.  He one day realized that, yes, he was doomed to die, and proceeded to decide that clearly eating an incredible amount of mangoes will stave it off.

monkey He’s trying!

Sadly, this didn’t work too well for him because fructose worsens aging related decline, and his results were lost to antiquity.

Humans continued with this desire, with ancient literature often toying with the concept of immortality.  The Epic of Gilgamesh, the worlds oldest surviving literary work from ancient Sumer, describe Gilgamesh’s efforts to attain immortality.  The Old Testament lists in the book of Genesis several early humans who lived hundreds of years, including Methuthselah, who lived to 969 and is the namesake of several anti aging endeavors.

The concept of the “Fountain of Youth” existed since since the 5th century B.C. in Greece, and persisted all the way until the famous journey of Ponce De Leon in 1513.  He traveled to the mythical land of Florida to find immortality, but unfortunately for him only found alligators and malaria (Disney world didn’t even exist yet!).

 The Fountain of Youth

Ancient medical practices often included herbs or practices which were purported to extend lifespan and improve vigor at old age.  This includes ancient Taoist practices, Ayurvedic medicine, Chinese traditional medicines, as well as the alchemists of medieval  times.  Though many of these remedies unsurprisingly fail when tested scientifically, the same mixing of meaningful medical value and pseudoscience can be said about the modern supplement industry as well.  Basic concepts such as exercise, healthy eating, and avoidance of stress were often present, and a few of the herbs listed have been shown to have medicinal value today (more on that in part 3).

In Newton’s time, Robert Boyle, discoverer of Boyle’s law of pressure and volume, posited that swapping old blood for young blood would rejuvenate the old.  He was right, as proven recently by Tony Wyss-Coray, and this is now a major subject of research.

Elie Metchnikoff is one of the first modern scientists to take an interest in aging.  Credited with the discovery of macrophages, he drank sour milk daily because he believed that the lactic acid would kill age inducing gut bacteria.  He died at 71 of heart failure.

Work by Clive McCay in the 1930’s showed for the first time that calorie restriction extended the lifespan of mice.  Little did he know that he had laid the groundwork for what is the most influential field of aging research to today.

In 1912 Nobel prize winner Alexis Carrel claimed that all cells were immortal, and attempted to prove it by keeping cultured chicken heart cells alive and growing for 20 years (longer than a chicken lives).  Though he succeeded, it is suspected that the live cells in his culture medium which he added continuously may have given a resupply.  The doubt stems from the fact that in 1961 Leonard Hayflick proved his theory wrong.

Leonard Hayflick (1961) to Cynthia Kenyon (1993).

hayflick.jpgLeonard Hayflick

In 1961 Leonard Hayflick cultured human fetal cells and human cancer cells in two seperate dishes.  The cancer cells continued growing indefinitely, but the non malignant cells stopped dividing after 40-60 divisions.  After this point, they reached a state known as senescence, where they acquired a strange and unhealthy post-mitotic morphology.  This is a landmark experiment because it is the first demonstration that aging occurs at a cellular level, opening up the field for study.

Though Hayflick didn’t know why the cells stopped dividing, the idea that the ends of DNA may be degraded during division was promoted by Alexei Olovnikov.  In the 1970’s it was shown by Elizabeth Blackburn that these chromosome caps are repeat sequences called telomeres, a discovery she later won the Nobel prize for.  In addition, in 1985 one of her students discovered that the enzyme telomerase can replenish telomeres and rejuvenate cells in a dish, allowing them to continually divide.  It is also the same enzyme expressed in most already immortal cancer cells.  Excitement blossomed and Geron company soon hopped up on to the scene and attempted to make anti-cancer therapies which inhibited telomerase and anti-aging therapies which promoted it. Sierra Sciences later joined in on the fray.

Unsurprisingly, their initial success in addressing this complex problem was limited.  Though studies in cancer resistant mice expressing telomerase do show extended lifespan, effective pharmaceutical activators have not been successful.  Telomerase gene therapy is in its first 1 woman clinical trial at Bioviva, but regulatory issues make gene therapy currently an inviable option in the USA.

The free radical theory of aging was common dogma at this time, leading to the idea that antioxidants in food may extend lifespan.  This theory has recently been essentially debunked, though antioxidants may still have health benefits.  Additionally, Roy Walford promoted calorie restriction from a scientific basis and was one of its first human practitioners for the sake of life-extension.  He lived to a respectable age of 80.

Additionally, interest in the life extension movement grew immensely in this timespan.  The Life Extension Foundation, a non-profit purveyor of supplements aimed at increasing the duration of healthy life, was started by Saul Kent.  They have one of the largest inventories among supplement merchants today and publish a monthly magazine. Also,  In 1991, the American Academy of Anti-Aging Medicine was founded to support the study of anti-aging medicine as an independent discipline, though this idea took a long time to get serious traction.  Besides, no one had extended the lifespan of any multicellular organism yet, so hopes for success still seemed distant.

Cynthia Kenyon (1993) to Aubrey De Grey (2007).

kenyon.jpgCynthia Kenyon

In 1993, a huge breakthrough shook the world to its core: UCSF professor Cynthia Kenyon created the first genetically mutant animal to live significantly longer, over twice as long in fact.

Her studies in C. elegans revealed the first definitive lifespan shortening gene, daf-2 (igf-1 receptor in humans), and the first definitive pro longevity gene, daf-16 (foxo-3 in humans).  Both of these genes lie in pathways effected by calorie restriction, where igf-1 is an insulin signalling receptor which assists in suppressing foxo-3 when nutrients are present.  This discovery would serve a large role in directing the focus of the anti aging field for the next two decades.

Andrej Bartke bred the oldest genetic mutant mice to date through interfering with the igf-1 pathway in 2004.  He won the Methuthselah Mouse Prize for mouse longevity in the process, a prize which still exists for anyone who beats him.

In 2003 David Sinclair discovered that sirtuins, a type of signaling compound in the cell controlled by NAD+, can promote extended lifespan in yeast when activated by resveratrol.  Resveratrol was later confirmed to extend lifespan in obese mice on a high fat diet as well. Resveratrol is a sirt1 activator,  but several sirtuins have since been suggested to have anti-aging effects, effecting calorie restriction signaling directly.

Resveratrol has since been shown to be ineffective at extending lifespan in healthy mammals, though more potent versions have been developed.  Sinclair himself founded a company known as Sirtris Pharmaceuticals to develop sirtuin activators.  In addition, the idea that sirtuin activators coupled with increased levels of NAD+ may be effective, supported by this 2013 paper, contributed to recent advent of a combination supplement marketed by Elysium Health.

The work of this era truly opened the door of the genetics of aging, tying together metabolic networks examined by Dr. Kenyon with potential treatments.  However, the Life Extensionists were never aiming for a simple mild increase in lifespan through supplement treatment.  The Immortality Institute, now Longecity (and where I initially learned about the anti aging movement in 2006), became a central internet hub for all who were interested in life extension, and many on it sought more dramatic approaches to the age old incurable problem.

Aubrey De Grey (2007) to Present.

de-greyAubrey De Grey

 

Aubrey De Grey, a heavily bearded englishman with a background in computer science and theoretical biology and a penchant for status quo breaking ideas, was slowly working his way up in the aging field in the early 2000’s.  His unusual background gave him a unique perspective, which he took advantage of when applying an engineering approach to aging in his 2007 publication “Ending Aging“.  Here he outlined seven different areas of focus which we must address to really see effective aging reversal in humans, along with potential ideas for action.

De Grey’s ideas, which focused around clearing different forms of molecular waste and damage in the body as well as protecting mitochondria quality, served as the to-do list for his Strategies for Engineered Negligible Senescence proposal which got him huge support from life-extensionists as well as several enemies in the mainstream scientific community.  He founded the SENS Research Foundation in 2009, which combines what in house work they can do with a significant amount of collaborations across the country.

Dr. De Grey and David Gobel popularized the idea of Longevity Escape Velocity, the concept that extreme lifespans are possible for those alive today if medical technology progresses quick enough.  He now has a somewhat revered stance among many life extensionists for his daring efforts as well as his wit and candor in explaining aging to the public.  In addition, several of the SENS targets now have widespread backing, in particular targeting senescent cells for destruction, destruction of amyloids, and breaking glucosepane crosslinks.

The science of aging has boomed in the fallout of the molecular biology revolution.

  •  Rapamycin, an FDA approved anti-proliferative isolated from Easter Island, is the most promising anti aging drug yet through its effects on the mTOR pathway (also linked to calorie restriction).
  • Metformin, a dirt cheap and relatively side effect free anti-diabetic drug with anti IGF-1 signalling and pro AMPK properties, is in the first official FDA approved (yet unsurprisingly underfunded) clinical trial to treat aging.
  • The National Institute on Aging even has an official program to test a slew of drugs on the mouse lifespan, the Interventions Testing Program.
  • Many new targets have been opened up which tie into the collective aging pathway, a now extremely complicated web of of signalling (here is a very simplified version).

In addition, the community optimism towards life and health extension builds, with a flurry of articles relating to the anti aging effects of different foods, supplements, and forms of exercise being disseminated each week to an increasingly expansive body of followers.  Senescence.info, a site by Dr. Joao Pedro de Magalhaes, now represents the largest and most accessible database on aging yet created.

Lastly, and perhaps most excitingly, aging is fast creeping into Silicon Valley.  In 2013 google announced that they were creating Calico, a massive project to work on developing drugs to treat aging.  They remain exceedingly secret, but investors are generally increasingly willing to give venture capital investments to aging research firms.

Final Thoughts

Aging research has clearly embarked on an incredible boom over the last 100 years, and is accelerating rapidly over the last 10.  We are on the verge of several things, including a transition into increasing acceptance of treating aging in humans and a general revolution in gene editing and regenerative medicine across the board.  However, we still need several things to drive progress forward, in my opinion:

  • Bold people willing to push therapies forward into clinical settings.
  • Rich people for donations and/or venture capital funding directed towards life extension efforts.
  • Tact people aiming to further increase awareness into the nature of aging and the advantages of life-extension.
  • Smart scientists who can tie the mountain of causes of aging together into a centralized framework while separating out the effects.

If recent trends persist it’s likely that we will have no shortage.

Stay tuned next week for a more in depth look at what actually happens when we age.

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