The Curse of Aging Part 2: Mechanisms

Overview

In the last installment of this series we went over the definition of aging and the history of its study.  Today, we will go into depth about what actually happens with age (observable effects) and why it happens (underlying molecular causes).

Aging, as we discussed, is defined by deleterious biological changes to an organism (us) occurring overtime.  First, let’s differentiate between two fields:

  • The study of Geriatrics is the medical discipline revolving around taking care of older patients with significant aging damage, generally known as the elderly.
  • The study of Gerontology is the study of the aging process itself. It includes characterizing changes that occur as a result of aging as well as the study of why, on a molecular level, they occur (generally referred to as Biogerontology). Biogerontology is largely what we discussed the history of in part 1.

Gerontology is at the heart of life extension-ism, whereas if the damage of aging is prematurely prevented or effectively reversed geriatrics would invariably go the way of the dinosaurs.

In this first section of this article, we will look at the phenotypes, or effects, of aging across the human body.  In the second section, we will learn the beautiful (if ugly) truth which inspires modern biogerontology: the same few processes inside and around cells cause all of the various effects across your body, from atherosclerosis to wrinkles. We’ll even take a crack at what those processes are, as scientists of the last few decades have for the first time truly begun to shine light on them.

Anatomy/Physiology

At least 12 defined organ systems can be defined in humans, listed below:

Image result for aging in different organsImage result for organ systems of the human body

Some tend to have a more powerful effect on health than the others, particularly the cardiovascular, pulmonary, immune and nervous systems.  The WHO statistics of the the top ten causes of death in developed countries lists cardiovascular complications as the top two killers, with pulmonary cancers and complications coming in at number three and five, and lung infections (likely deadly due to immune deficiency) as number four.  Also on the list is Alzheimer’s, several digestive system cancers, and diabetes.

An important point, to make, however, is that organ systems do not act independently and thus all contribute towards whatever pathology people eventually succumb to.  People don’t tend to die of endocrine failures, but altered hormonal signalling weakens all systems substantially and can promote cancer.  Digestive issues prevent proper nutrient uptake and toxin clearance, leading to tissue damage across the board.  Immunodeficiency is strongly associated with cancer, and renal issues can both be deadly on their own and contribute to multiple system failures due to waste accumulation and improper control of electrolytes.  Muscles and bones help us exercise and stay healthy, and the aging of the skin increases risk of infection.

Perhaps the most important point, though, is that all forms of aging can cause suffering regardless of their contribution towards risk of death, so they must all be addressed.  Let’s take a look.at the unique way each system degenerates:

Integumentary System

This is our skin, hair and nails, the part of us everyone sees at least a little of.  Thus, it is also probably the most preoccupying when it ages, as the Rogaine and Botox industries will attest to.  All things considered though, our skin is an incredibly important organ.  With aging, it:

  • Becomes less effective at producing sweat, potentially leading to dangerous overheating. Also becomes drier, thinner and less elastic, tearing and bruising more easily and potentially becoming weaker at preventing infections.^
  • Becomes pretty much the most cancer prone organ in white people.

Thus caring for your skin is not just a sign of keeping your Baywatch dreams alive (speaking of, wear sunscreen!).

Here’s a diagram:

Image result for young vs old skin

And, balding is important too. No more dressing up as a night elf at cosplay festivals.

Skeletal System

As most of us know, our bones get weaker with age.  One may wonder, “how do bones get weaker with age?  People find bones that are hundreds of years old all the time!”.

The answer is simple: while we are alive, our bones are a dynamic organ.  They require their own blood supply, and are constantly being remodeled by cells called osteoblasts and osteoclasts.  Osteoblasts lay the minerals and increase bone density, and osteoclasts eat it back up while reducing the density.

As we age, our osteoblasts start to fail and our osteoclasts pick up steam.  The result is a disbalance in the equilibrium, where there is a net loss of minerals.  The extreme of this is osteoporosis.

Image result for osteoporosis

Lymphatic System

The lymphatic system is primarily an immune system, being necessary for the maturation of lymphocytes and effective adaptive immunity.  Failure of the adaptive immune system results in increased risk for disease, and increased mortality from diseases like pneumonia.  Basically, as your aging immune system fails you become closer and closer to bubble boy (but without a bubble).

Image result for bubble boy

In addition, cancer’s increased occurrence with aging can be tied in part to failure of immune surveillance^.  Immunosenescence is a serious condition and among the most critical aspects of aging to address.

The thymus, our organ which trains T-cells (our knights against viruses and cancer), dies young and quickly of its own accord.  It shrinks to a negligible size in the third decade of life, a process known as thymic involution. Our T-cell troops are still there but the army becomes outdated in its tactics without the thymus, a process driven by the lack of naive T cells which can adapt to new invaders.  A larger and larger percentage of the pool becomes dedicated to fighting latent infections like CMV over time.

Lymph nodes, needed for the maturation of both B cells and T cells, also may degenerate.  Lymph channels, which have a role in clearing waste around the body, become less effective.

In addition, the bone marrow, which produces all lymphocytes as well as leukocytes and red blood cells, ages significantly.  The stem cells present in the marrow may become senescent or die, and a smaller and smaller number of clones are involved in creating all your blood cells.  They increasingly receive signalling from the wrong niche, producing more leukocytes and less lymphocytes^.  And they frequently cause cancers such as leukemia and lymphoma.

Respiratory System

Our lungs.  Most people just remember these commercials of the people with the cool obsidian textured lungs:

Image result for smoker lungs

The thing is, lungs age with or without smoke inhalation (just way faster with).

Image result for lung aging

Progressive failure of pulmonary function is labeled COPD, essentially the end stage of normal aging decline in the lungs.  This is strongly accelerated by smoking.

And, of course, death from lung cancer is the most common form of cancer death in the US.  It is less common overall than prostate cancer in men and breast cancer in women, but more deadly than either.

Muscular System

Sarcopenia occurs when skeletal muscles shrink during aging.  Reduced signalling from pro-anabolic hormones such as testosterone contributes, as does impairment of stem cells involved in skeletal muscle repair known as satellite cells ^.

Image result for sarcopenia

Sarcopenia is one of the most visible symptoms of aging.  Though to some extent accepted as natural, muscle wasting is a huge contributor to frailty and reduced quality of life ^.

Nervous System

The nervous system is composed of a mix of several different cell types, including:

The first three cell types have all been implicated in the complex pathology of neurodegeneration. Neurodegenerative diseases include Alzheimer’s, Parkinson’s, ALS (Lou Gehrig’s disease), Huntington’s, and FTD.  While they each affect different parts of the brain and thus have different neurological symptoms, they all include a mix of astrocyte dysfunction, insoluble protein accumulation, microglial inflammatory responses, and progressive neuronal death^^.  They occur with various frequencies, with Alzheimer’s being almost the default given enough aging in the brain and Huntington’s being a more specific genetic disorder.  Most importantly, they are all the worst things in the world.

They also all have nothing but (weakly) palliative treatment.  I’m not sure if the FDA is just extra concerned with side effects of potential treatments or what, but if I had Alzheimer’s and the one drug that can cure it had a 50% chance of resulting in the baby alien from the movie Alien exploding out of my skull I would still not think twice before taking it.

One recent study, however, known as the MEND trial, saw positive results with Alzheimer’s after adjusting many nutritional parameters and correcting nutritional deficiencies/ adding anti aging supplements.  It’s important to realize that in the end, neurodegenerative disorders are the end stage of aging in the brain.  Genetically normal young people do not get Alzheimer’s, and likewise each and every elderly person has at least some of the pre-clinical symptoms (amyloid accumulation in particular)^.

download

Your brain on Alzheimer’s.

Digestive System

Basic changes which everyone knows about include tooth decay/gum disease and increased constipation^.  However, another common and particularly insidious issue is inflammation in the intestines resulting in reduced nutrient uptake (which will exacerbate symptoms across the body)^.  Cancers of the stomach and colon also grow increasingly common with age.

Liver damage with aging is also a serious issue.  Fat accumulation in the liver along with inflammation from a number of factors (hepatotoxic drugs, hepatitis C exposure, alcohol intake, etc) can lead to scar tissue eventually replacing the normally highly regenerative liver tissue^.  The young liver can do most of it’s metabolic work at 20% efficiency, but liver failure is still a common cause of death in the elderly^.

Image result for liver disease

Urinary System

Particularly infamous in the urinary system is the prostate, an organ which represents the most common cause of cancer in men.  I say the organ is the cause, given that studies have  that 50% of men age 70 to 80 have malignincies present according to autopsy studies^.  If cancer doesn’t occur, benign prostatic hypertrophy can make it hard to pee^.

The kidneys are strongly effected by aging as well, with kidney function declining significantly^.  Crosslinking of kidney tissue is a problem because it prevents proper removal of waste across barriers to be excreted.  This is a particular problem in diabetics^.  For those for whom the kidney represents the Achilles heel of their aging physiology, dialysis in the only option until end stage renal disease eventually defeats them.

Endocrine System

Many hormones change their expression with aging.  Some people supplement with human growth hormone, testosterone, and/or estrogen to maintain youthful beauty and function.  Deficits in these hormones are associated with negative effects, but replacement can come with its own problems including risk for hormone dependent cancers^^^.  Here is a list of some hormones which change expression with aging (not exhaustive, mostly just well known ones):

Reduced

Increased

Source for all not specifically sourced above: ^

The most well known aspect of endocrine aging, however, is the increase in insulin resistance and the rise of Type 2 diabetes.  This is one of the most readily modulateable symptoms of aging, but for those who do not actively take precautions diabetes is essentially a form of accelerated aging in and of itself.  Diabetes will strongly increase risk for heart failure, atherosclerosis, dementia, kidney disease, neuropathy, blindness, and probably other things not explicitly listed as well^.  In part 2 of this article this will make more sense, as insulin and insulin-like peptide signalling and sugar associated crosslinks are both fundamental to the aging process.

Cardiovascular System

The aging of the cardiovascular system is notorious for causing the largest percentage of deaths in modern society, directly via heart attacks, strokes, and progressive heart failure, as well as indirectly in dementia^.

The most common issues underlying cardiovascular risk are atherosclerosis and high blood pressure (which also contribute to each other).  This is the classic “hardening of the arteries” syndrome, where cholesterol occludes blood flow and prevents proper elasticity of the vessel wall while increasing blood pressure^.

images-jpg-coronary-artery

Luckily, cardiovascular disease risk can be mitigated by many life style factors, and those who eat particularly healthy and exercise while avoiding smoking have a leg up^.

On the other hand, one form of heart disease particularly common to the oldest of old involves accumulation of the transtherytin amyloid protein in the heart which causes dysfunction and death as it accumulates.  This is the pathology behind “senior systemic amylodosis“, how most of the genetic lottery winners who have survived everything else end up dying^.

Male/Female Reproductive System

Female reproductive capacity famously jumps off of a cliff during menopause, but male reproductive capacity also is reduced with aging^.  Genetic alterations in gametes contributes to an increased risk of birth defects in older parents^.

The underlying cause

Though each system appears to fall apart in its own manner, specific underlying cellular causes appear to be similar in each case.  Broadly, cells begin to lose energy, signal within and without less effectively, accumulate waste and stimulate inflammation^.  The fact that many treatments like calorie restriction and exercise have so many benefits across tissues is a testament to the common nature of the menace.  Now, we will look into that deeper nature a bit more closely.

Part 2: Molecular Aging

In 2013 Steve Horvath proved, via analyzing complex patterns of DNA methylation in a man and woman and comparing them to an array of people of different ages, that tissues actually age at different rates.

DNA quality (relative methylation patterns) by tissue

Image result for aging by tissue

This is mainly just interesting as well as a potential biomarker of aging damage, but highlights the fact that there are fundamental similarities in all aged cells at the level of individual genes effected.  The hematopoetic stem cells that create your blood become senescent in largely the same was the stem cells in your brain do, though one situation causes immunosenescence and one forgetfulness.  Diet and exercise have similar effect at improving health in muscle tissue, brain cells and heart tissue.  What’s behind all of this?  It’s simple.

Biochemical Pathways of Aging

Image result for aging pathway

See? Simple!  Well, I guess not everyone wants to go down that rabbit hole.  Let’s look at a simplified version:

Image result for aging pathway

The pathways above are important because many interventions which currently exist and have a beneficial effect on mean/max lifespan work through them, and because they appear to impact cells across the body more or less ubiquitously.  These include:

  • Calorie Restriction, in green, which activates AMPK and deactivates mTOR.
    • MToR complex 1 is the closest thing to a master regulator of metabolism that a cell has.  When turned on, protein synthesis is stimulated and anabolic activity is promoted.  When it is deactivated, cell growth is slowed or halted and repairing activities like autophagy are promoted.  MToRC1 is also an essential molecule for cancer growth and its inhibition has been associated with reduced cancer incidence and severity ^. Its inhibition results in increased lifespan^.
    • AMPK is stimulated by exercise and the anti insulin resistance drug metformin, and has the effect of enhancing transcription of sirt1, enhancing autophagy, improving insulin sensitivity and reducing cell proliferation^.
  • Insulin Signaling, in blue, driven by both Insulin as well as the the ultimate pro aging molecule IGF-1 mentioned in part 1, which was mutated in Cynthia Kenyon’s original long lived worms and Andrzej Bartke’s long lived Methuselah mice.  It also represents a large part of why type 2 diabetes is accelerated aging.
    • High insulin signalling levels promote cell division and inhibit repair mechanisms, being associated with both aging and cancer^^.
    •  FOXO3, a transcription factor, is among the most important downstream targets and is required for the extended lifespan of insulin mutant worms^Klotho is an important modulator of FOXO3 and works against aging^.
  • Inflammation: Inflammation signaling is generally damaging and increases across tissues with age.  Inflammation reducers like curcumin (turmeric) and aspirin are suspected to have beneficial effects on age-related disease^.
  • Oxidative Stress/ Mitochondrial Signalling: Oxidative stress, once thought to be the main driver of aging damage, is now suspected of being necessary for a protective hormetic response^.  However, an exception may exist in the mitochondria, whereas mitochondria-target antioxidants have shown to slightly extend lifespan^.
  • Telomere and Genome Maintenance: Many of the nuclear enzymes involved in genome maintenance listed above repair DNA, and mutations can cause both premature aging and cancer.
    • Telomeres:  Mentioned in part 1 of this series, telomeres are established, essential components of chromosomes which become damaged with aging through stress and multiple rounds of cell division^.  Mice engineered to replace their telomeres have extended lifespan^, and the (1 woman) company Bioviva is trying to take a similar route in humans.
    • Werner’s syndrome, where patients tend to show old age phenotypes in their 40’s and usually die of cancer, is caused by a mutation in WRN, a gene needed for effective DNA repair.
    • Huchinson-Gilford Progeria Syndrome patients like Sam Berns, the most striking early agers, have a mutation in LMNA and die by 20 of atherosclerosis (this protein is also increased in abundance in the cells of normal old people^).  This protein is important for nuclear structure and chromosome arrangement.
    • Retrotransposons, self replicating aspects of our own DNA, have been seen to increase activity and number with age and cause damage^^.
    • Repressive epigenetic signatures such as H3K9, meant in large part to protect our genome from damage and aberrant expression, are reduced with aging^.
    • SIRT6a protein associated with promoting DNA repair and telomere maintenance as well as reducing inflammation, extends the lifespan of mice by ~15% and causes a premature aging effects when mutated^.

This list is by no means exhaustive, but represents some of the most thoroughly studied pathways.

Advantages/Disadvantages of the Pathway Biology Approach

Advantages:

  • Molecular biologists are good at dissecting and deciphering genetic pathways, so we have the tools to dissect aging from this angle well developed.
  • Many druggable targets arise, quite a few of which can be targeted through lifestyle factors, food or supplements.
  • Many long existing approaches to avoiding age-related disease rely on these pathways.
  • Many of these pathways are tied with cancer and thus we could be winning multiple battles at once.
  • Insights are beginning to arise at how all these factors tie together, helping exceptional scientists discover what the most fundamental causes of aging may be, and how we can treat these.

Disadvantages:

  • Dissecting genetic pathways can lead to obsession with anomalous details and useless systems biology information dumps, capable of getting NIH funding but not improving anybodies life.
  • Pathway biology does not effectively address some anomalous and case specific effects, such as thymic involution and T cell senescence, menopause, and how to treat hormonal deficiencies.
  • You can attempt to drug the hell out of everything studied for aging related effects, and you will look like this guy below.  And you’ll still need a singularity to live forever.

Image result for Ray Kurzweil pills

The Damage Thoery of Aging

SENS, an organization started by Aubrey De Grey to target aging damage at a molecular level, follows the following 7-step model of aging damage.  This represents one of the first and only attempts to holistically compile a list of age related molecular alterations.

  • Glycosens– The accumulation of tissue stiffening cross links occurs in all tissues over time.  These are largely created from what are called glycation reactions, non-enzymatic reactions driven by glucose and other sugars.  Glucosepane is a particular common type of crosslink which represents over 90% of total crosslinks in the body^.  These crosslinks are not naturally reversible, and their buildup stiffens tissue and reduces function.
  • Amylosens– Amyloid proteins are normally soluble, but can become folded in a way which causes them to stick together and form fibrils.  They can accumulate in extracellular space and cause damage when not removed or degraded.  The most famous amyloid is certainly  amyloid beta-42, which accumulates in the brain of alzheimers patients and causes damage, but other amyloids such as transtherytin amyloid also cause significant damage in aging.
  • Lysosens– Lysosomes are the organelle most responsible for eliminating garbage in our cells.  They become clogged with a mess of undegradeable compounds known collectively as lipofuscin due to a combination of signalling changes, increased loads of damaged proteins, and internal dysfunction^.  When this occurs, the function of the entire cell is impaired due to reduced quality control.  A similar situation occurs with proteasomes, smaller cellular structures which degrade individual proteins^.
  • Mitosens–  Mitochondria are damaged everyday in our cells, but they generally are degraded in the lysosome when they become truly dysfunctional in a process known as mitophagy.  However, impairment of mitophagy as well as accumulating damage in mitochondrial DNA itself results in sick mitochondria with reduced function during age^.
  • Apoptosens– Cells which are damaged with aging often acquire what is known as a senescent phenotype, where they are functionally impaired and unable to divide.  Senescent cells may also release inflammatory factors and damage surrounding tissue, rather than just taking up space^.
  • Replenisens– Representative of the general need to replace lost cells, replenisens is broad and alludes to all the stem cell work currently being done in labs across the world.  Among the most well known and important cells lost to aging are stem cell populations such as hematopoetic stem cells in bone marrow or satellite cells in muscle.  Certain age related diseases such as Parkinson’s result entirely from a loss of a single population of cells.  Both dividing cells and non dividing cell populations may die with aging, and both must in principal be replaced at a certain point to prevent dysfunction.
  • Oncosens– Broadly, cancer occurs with aging as a result of multiple factors including a weak immune system, inflammation, pro-oncogenic genetic and epigenetic changes in individual cells, and dysregulation of metabolism^.  Generally, it’s better to target cancer before it arises than to fight a painful battle against an evolving tumor.
  • Genetic issues: We listed multiple forms of genetic damage earlier when discussing the molecular biology of aging.  Pathway biology approaches have begun to trace back to fundamental genetic and epigenetic causes^, which are forms of damage on their own, and in some ways genetic damage could potentially represent a bridge for the gap between philosophies.  SENS has not focused on damage at the level of DNA.

Advantages/Disadvantages of the Damage Approach

Advantages:

  • Blunt force approach. Address the issue directly, don’t waste money glossing the details.
  • Potentially extend lifespan much farther through reversing otherwise irreversible symptoms rather than simply slowing their progression.  In the end, this is the only way to radical life extension, as current evidence suggests that the crux of aging pathway biology is largely to reduce damage in the first place^.
  • Many will be one-time or periodic treatments rather than daily supplements, and thus could potentially be less of a hassle and even cheaper^.
  • A cool guy with a beard told you so^.

Disadvantages:

  • The technology required to address issues at a damage level, like gene therapy and stem cell treatments, are rapidly becoming feasible but face more technical and regulatory hurdles.
  • We can currently only estimate how many sources of damage in need of targeting exist, as well as their relative importance.

Tying it Together

As the molecular biology of aging is itself largely a process of damage mitigation, at least on some fronts, it is evident that damage based theories must be addressed for radical life extension.  Thus, while those looking to extend healthspan tend to be content with the pathway biology, life-extensionists and immortalists are discontent sans a damage based, sledgehammer approach.

In the end, however, it is likely in anyone particularly interested in life-extension’s best interest to eschew both approaches.  Even if radical rejuvenation technologies are the end goal to cure damage, living an extra healthy lifestyle with proven long life compounds thrown in will cut damage occurring in the first place.  It will cut the risk of early death down significantly, and may extend your personal maximum theoretical lifespan a bit.  As long as it doesn’t stress you out or bankrupt you, it will likely increase your chance of reaching the age of robust rejuvenation therapies and help you achieve Longevity Escape Velocity.

Thus, next month we will go into depth about the methods to treat aging across the board, those that work, those that don’t work, those that could, and those that couldn’t.  In the meantime, if you are interested in learning about the science of aging at greater depth or following the movement, here are some valuable links:

Academic Reviews:

This awesome review: Riera CE, Merkwirth C,  João Pedro de Magalhães, “Dillin A, “Signalling Networks Determining Lifespan”, Annual Reviews of Biochemistry, Jun 2016.

http://www.sciencedirect.com/science/article/pii/S0955067417300017 : Thomas Rando, Anne Brunet, “Interaction Between Epigenetics and Decline in Aging Stem Cells”, Current Opinions in Cell Biology April 2017.

https://www.ncbi.nlm.nih.gov/pubmed/27729586 : Amigo et al, “Mitochondrial Form, Function, and Sigaling in Aging” Biochem J Oct 2016

Organizations:

www.sens.org

Non-Academic:

http://www.senescence.info/:  João Pedro de Magalhães, a senior lecturer of aging at Liverpool who did his postdoc with the legendary George Church, made this site to catalog essentially all information available into one database.  Includes info on long lived animals (a topic for another time on this site), human longevity genes, gerontology organizations and companies, leaders and entrepreneurs in the field, molecular aging studies, and more.

 

http://www.longecity.org/forum: The number one site for the life extension community, with a highly active forum and a range of viewpoints/backgrounds.

www.fightaging.org: Continuous updates on new discoveries in aging research.

http://www.anti-agingfirewalls.com/: A blog dedicated to examining the most detailed intricacies of aging biology and how they fit together.  Requires a biology background.

And here is a link to related articles on Beneaththenoise:

https://beneaththenoise.com/2016/12/12/the-curse-of-aging-part-1-definition-and-history/ 

Standing at the Seashore, by Richard Feynman

There are the rushing waves, mountains of molecules, each stupidly minding its own business.  Trillions apart, yet forming white surf in unison.

Ages on ages, before any eyes could see.  Year after year, thunderously pounding the shore as now. For whom, for what? On a dead planet, with no life to entertain.

Never at rest, tortured by energy, wasted prodigiously by the sun, poured into space.  A mite makes the sea roar.

Deep in the sea, all molecules repeat the patterns of one another, till complex new ones are formed.  They make others like themselves, and a new dance starts.

Growing in size and complexity, living things, masses of atoms.  DNA, protein, dancing a pattern ever more intricate.

Out of the cradle, onto dry land, here it is standing: atoms with consciousness; matter with curiosity. Stands at the sea, wonders at wondering.

I, a universe of atoms, an atom in the universe.

Soul of Protest

Our grandmothers, devoid of their brother’s power,

there voices their soul armament

stood spartan for the longest hour

broke no emotion speaking their discontent.

Ancestors who simply stepped on a bus, refused to give up

tired of being treated as dogs of the street

stone faced and unflinching, through fire they stood up.

They had a dream, togetherness replete.

What’s happened since then? Now humor is our sword?

Insults about hands and hair?  Is that the cause the world will see?

Loud music and hooting, stealing and looting, it’s a party for when we’re bored?

Now we fight to be popular and clever? Our elders fought to be free.

Today we post pictures of our protest to facebook and we hope for likes,

Yesterday their only metric was liberation through the hard fought fights.

 

This is in response to what I saw at the NYC women’s march on the Saturday after Trump’s inauguration.  Perhaps my sample was not representative, but at what I thought was a march for women’s issues ended up being 75% signs trying to find the cleverest way to insult president Trump, often insulting him in the same petty ways he has insulted others.  To be fair, I am not a person in a particularly disadvantaged population. Nonetheless, this worries me in general as part of a trend where self indulgent 1-upping political humor, online trending articles, and buzzwords are beginning to supplement serious education on issues, free thought, and gandhi-esque efforts rooted in egoless sobriety in the progressive movement.  This has even been punctuated at occasion with drunken anarchy and rebellion at times since the election.

I’m sorry to the many, many people standing up for issues who do still aim to make protesting not something about ego, but about strategically bettering society.  I love you all.

 

 

Plans for 2017

So, finding myself bogged down on writing an extensive second section for the Aging Research piece, I’ve decided to partition each months blog entries more definitively into 1 larger and 3 smaller pieces.  This will include:

-1 poem from myself

-1 poem reiterated from someone else

-1 short (~8-10 paragraphs) biographical description of a great scientist or inventor.

-1 long piece on a scientific subject, including the history of how it got that way.

Here are the plans for each month:

January:

-Aging Part 2: Physiology and molecular biology of aging

Richard Feynman

February:

-Aging Part 3: Current interventions and future therapies

Leonardo Da Vinci

March:

-The rise of the C. Elegans research community

-John Sulston

April:

-The evolution of the nervous system

-Santiago Ramon y Cajal

May:

-Ancient medical systems in Europe, the Middle East, China, and India

Elon Musk

June:

-The history and current study of mind altering drugs for psychological therapies

Nicolas Tesla

July:

-The psychological and neurological study of attention

-Tycho Brahe

August:

-The evolution of the theory of evolution

Pythagorus

September:

-Neural correlates of gender and sexuality

-Gregor Mendel

October:

-Hormonal systems and their evolution

-Isaac Newton

November:

-Hominid and early homo sapien evolution

-Wright brothers

December:

-The evolution of humans in the last 100,000 years.

-Sydney Brenner

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 in a total of less than 15 minutes of reading each (because reading about aging reminds us that our time is precious ).  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 about as good as Life Extension magazine 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 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 evolution.

  •  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 diabetic drug, is in the first official FDA approved 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.
  • Efforts 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.

Light through the Prism

The light of God, the first light, the original color, flows through the prism of consciousness and is refracted into the colors of 10,000 things.

It is that this prism is kept clear that each color is sacred, free, eternal. The view is as the lord of life in technicolor, splashed on each leaf, crumbling only by the wind.  It is that this prism is translucent that each faded color may remind us only of the light we lack, and through our ignorance we dream it clear.

It is through love that the eyes of another mirror these 10,000 things, again as one beam if no frequency is lost in translation. As once left through the back, now comes in through the front, visible in full.

And that this prism is opaque that there is not but flesh in the reflection.  It is the most taunting void to fill, the most haunting of mirages.  But in the end, the source shall shine on always.

Om Mani Padme Hum

Recently, on a trip to India with my girlfriend I went to a state known as Sikkim, a small Himalayan kingdom which joined the republic in 1975.  The culture is very different than the rest of India, with Tibetan Buddhism being the predominant religion and significantly more Tibetan, Nepali, and Chinese influence overall.  It was both a particularly tranquil and beautiful place.

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Kenchenjunga Falls

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Main market street in Gangtok, the capital.

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Prayer flags dotting the forest at the spot in which the kingdom was originally founded in the 1600’s.

Our journey was made logistically easy by a taxi driver who took us all around for the whole 5 days, a nice guy who seemed totally immune to anger, impatience or exhaustion. This is despite the occurrence every 15 minutes of a car coming in the opposite direction which forced us approximately 6 inches from the cliff which inevitably lay beside the road.  Every morning he would play a particularly nice sounding mantra, almost a song but with only 4 words.  It relaxed me and came to represent the tranquility of the place within 3 days.

One day in the capital city of Gangtok my girlfriend and I walked in to a Buddhist temple grounds, touring around briefly before continuing.  On the side of a pillar we saw this:

Syllable Six Pāramitās Purifies Samsaric realm Colors Symbol of the Deity (Wish them) To be born in
Om Generosity Pride / Ego Devas White Wisdom Perfect Realm of Potala
Ma Ethics Jealousy / Lust for entertainment Asuras Green Compassion Perfect Realm of Potala
Ni Patience Passion / desire Humans Yellow Body, speech, mind
quality and activity
Dewachen
Pad Diligence Ignorance / prejudice Animals Blue Equanimity the presence of Protector (Chenrezig)
Me Renunciation Greed / possessiveness Pretas (hungry ghosts) Red Bliss Perfect Realm of Potala
Hum Wisdom Aggression / hatred Naraka Black Quality of Compassion the presence of the Lotus Throne (of Chenrezig)

“Om Mani Padme Hum”, a term I hadn’t ever heard before.  However, I read it and contemplated for 5 minutes, primarily the first 3 columns as the deities and samsaric realms had little meaning to me.  Eventually we continued on our way.

Next morning, we got into the car and heard the mantra song again.  Suddenly I burst out with excitement; I realized what the words were!

I felt compelled to continue listening to the song after we left Sikkim, and after we left back to the states.  It would be particularly nice to listen to for 20 minutes as I began work in the morning, or as running music.  Additionally, and perhaps more importantly, I believe the idea behind it has particularly meaning in chaotic times such as these.

Here is the Dalai Lama’s words about the mantra:

He interprets “mani padme” primarily as one entity, a jewel in a lotus flower.  Lotus flowers have many meanings in Buddhism, but I’ve understood the meaning to be something along this zen verse:

“May we exist in muddy water with purity, like a lotus.”

Likewise, jewels have a specific meaning in Buddhism, with the “three jewels” representing dharma (duty), teachings, and Sangha (community).  By this simple picture, mani padme can be viewed as the growing brightness of correct actions, given time, and purity despite the excess of mud in the world.  Let’s dissect it further, though, to the original chart:

  • Om (Generosity): Om is a shared syllable throughout vedic religions, sometimes interpreted as the sound of the still universe.  Hinduism associates the term with Atman (soul) and Bhraman (Ultimate reality, or God depending on interpretation).  Here is the symbol in Devanagari, which I’m sure you’ve seen before:

om

The relationship of generosity, in my opinion, is that empathy is a the base of all meaningful action and decisions.  The soul of a human being evolves by recognizing the value in other souls, and by holding this as the only foundation of our action we can choose rightly when we must make difficult decisions.  It is not even a prelude to pacifism or absolute non-violence in this sense, as Ahimsa does not traditionally teach this. Instead it is a basis to go into a peaceful day with love and kindness and to go to war as a last resort, as if going to a funeral.  Additionally, seeking stillness in our own body and mind is the basis for health and activity.

The opposite is pride and ego, where we draw ourselves according to something arbitrary, see this as the all encompassing good, and limit compassion accordingly.

  • Ma (Ethics):  I assume this traditionally means something along the 8-fold path for monks, but for us Westerners I believe ethics means something along the line of a concentrated plan of action driven from the base of generosity.  This can be our commitment to work, loyalty to our friends, and the plethora of actions taken to keep our lives effectively in order (chores, working out, meditation, proper diet, management of money, etc).  And of course, this is in thought, word and action.
    • The opposite is of course jealousy and lust for entertainment, the emotions of impulsiveness which sacrifice the long term for the short term.
  • Ni (Patience): Patience is meaningless without ethics, and visa versa.  Patience is simply the fortitude required to go without reward for some period of time without giving in.
    • Passion and desire are the opposites, for what I assume to be similar reasons to what is listed above.  It’s notable that the more passion we have for something, the more we need to see the reward from it to sustain that passion.
  • Pad (Diligence):  This to me is interpreted as an important subset of awareness.  Meditation, for example, simply asks us to become aware of our negative thoughts, notably those driving us away from our base and thus our duties indirectly.  Diligence is neither confined to a specific timepoint nor to our thoughts, but is meant to be all encompassing.  We can sometimes say things which have subtle undertones which we fail to pick up on, or experience tenseness in our body or fidgeting legs from discomfort.  It’s solely our duty to account for this.
    • Ignorance and prejudice are some of the first thoughts that arise in the subconscious mind.  Look right now into your thoughts, count for 60 seconds, and it’s likely you’ll notice at least 1 prejudiced or ignorant thought arise against another person or group.  And the correct response is not “well I’m right”.  To be diligent is simply to acknowledge that it exists.
  • Me (Renunciation):  This evolves from diligence because it is the conscious choice to reject the ignorance and prejudice which you become aware of.  It is also necessary to renounce excesses.
    • Greed and possessiveness tell us that renouncing something will mean that we are at a disadvantage compared to others who are allowed to have it.  People may feel subtly that they want to feel anger toward another person who is feeling anger towards them or even towards others.  Possessiveness tells us not to give up what others want or have, even if it is harmful.
  • Hum (Wisdom):  Wisdom is the icing on the cake, whereas this particular cake tastes totally bland without icing.  It is the deeper understanding of the world which enables us to elevate the quality of thoughts and actions beyond where they were before.  It is also only truly possible to reach higher levels of understanding if we are working effectively and patiently while staying aware and pure from distractions.
    • Wisdom relies on the base of generosity, and this understanding of the base is toppled through hatred.  Hatred rejects the inherent existence of a soul in others, labeling them as a pimple to be removed.  Yet still we see the world reflected accordingly.

This is my understanding after having contemplated the meaning and applied it to my life for the last few weeks.  The jewel in the lotus flower is a thriving human being, growing only from compassion and shielded only by wisdom.

However, how does this apply in everyday life?  Let’s take a brief look at 2 scenarios.

  1.   One is sitting in work, doing the tasks required, but seeing little return, or no longer valuing the return which is coming.  Bitterness is welling up, and productivity is going down as frustration and helplessness grow.  At worst, a sense of ennui and nihilism begin to creep in.
    • Om:  What are your priorities, and who is this work benefiting?  Focus on how the little things help the world.
    • Ma: Focus on the task at hand and know that you are not only better than the impression your own weakness gives, but your decision to do your duty is standing alone anyway.
    • Ni:  Patience is not something you are inherently without.  What is distracting you?  Are meaningless pleasures and distractions across your life bringing you from focusing?  Are you not, to a degree, using these as a pick me up in the first place?
    • Pad:  What exactly is it that you are thinking in work?  What are you doing to procrastinate?  What are your thoughts of disappointment saying, word for word?  If you have 5000 negative or distracting thoughts in a day, endeavor to recite them all at the end of the day.
    • Me:  Which of these distracting or disconcerting thoughts that you have are actually helping you?  Throw the rest away, fully.  But keep any legitimate grievances.
    • Hum:  Why did you go into you job in the first place?  Remember the little details, the big picture.  In past and in future.  Know what you are doing with your life and why, and if it no longer is worth it, given Om Mani Padme Hum, give it up for something better.
  2.  The political scene is chaotic.  The right wingers in the government and in the media are not all bad, but it seems to be split between out of touch ideologues and conspiracy theorists whose minds are on an infinite negative loop.  The left wingers in power are generally much better in my opinion, but still largely ignoring cries from the populace while relying on political correctness and identity politics while this past election shows that this truly just masks people’s true feelings.  And, everyone in the country is yelling, with a lot of people on both sides saying extremely nasty things.
    • Om: Remember that the purpose of the government is to reduce human suffering, whether you like it big or small.  Remember that your words should be motivated by compassion, and if you are putting people down on the internet or verbally you are not actually changing anything except the degree if compassion in yourself.  That includes people saying useless things about muslims and hispanics, as well as white people and trump supporters (if you are comparing the weight of the two in your head right now, reread this paragraph.
    • Ma: Your main life duties have not gone away.  But, do you want to make a difference in politics?  Consider carefully everything you do. Consider the outcome and the means at once.  Don’t waste energy punching a wall, either.  Consider that your inner turmoil may indeed be your inner roller coaster.
    • Ni:  Patience means doing what you can while your opponents in power rather than praying for anarchy in the mean time.  It means doing little things like writing a representative even though they won’t write you back.  Because civic duty is unrewarding.
    • Pad:  Keep an awareness of the actual intent behind what is published in the news and what leaders say.  But most importantly, keep an awareness of every point that prejudice comes up in your own thoughts.  What is this doing besides complicating things?
    • Me: Renounce anger and prejudice.  Renounce obsessive thinking.  Renounce violent protest on the streets and in your own head.  And renounce complicity as well.
    • Hum:  The crux.  Educate yourself in history and economics.  In religion and modern warfare.  In geopolitics and in culture.  If you have your head on straight after the rest of the chant, and you remember your base, you can have a solid opinion with the prerequisite knowledge.  You can support a given war and not condone hatred, because you are coming from the right place.  Or you can not.  You can support stricter immigration policy without resenting minorities. Or not.  Either way, you can enjoy your life and be content that you have walked the best path as well as you could.