If it seems as though research in to aging is exploding right now, that’s because it is.  Over the last few decades, our paradigm on aging has experienced a pretty substantial shift.  What was once believed to be an inevitable process dictated solely on the passage of time and the genetic hand you’ve been dealt has now transformed in to something we may be able to exert some level of control over.

Don’t get me wrong, you’ll eventually die, we all will.  The question is, when will eventually come?  If you’re like me, you’d like eventually to come later rather than sooner, provided you do so without a chronic disease or disability.

Over the last decade, I’ve put tremendous effort in to finding a way to increase my health and lifespan without having to put a tremendous amount of effort in to doing something that makes life less enjoyable.  I don’t want to starve myself every day, I don’t want to completely remove fun things from my diet, I don’t want to exercise 10 hours a week, and I’d like to enjoy craft beer on the reg.

Can I continue to do this without substantially speeding up the aging process?   That’s something I hope to find out.

We are beginning to creep ever so slowly in a direction where there may be some fairly significant therapies we can pursue that can lead to substantial life extension.  I’m pretty sure this will happen in my lifetime.  There are 2 ways to take this:

1. I want to maintain my health until that point so that when I undertake these therapies I’m still robust and healthy
2. I’m going to throw caution to the wind and hope they can fix whatever I do to myself in the next 30 years

If you’re like me you find yourself somewhere on a continuum between the 2, probably closer to #1 on the weekdays and closer to #2 on the weekends.  If you were to ask me 10 years ago, I would have thought that it wasn’t possible to do both.  With calorie restriction being the gold standard for optimal longevity and healthspan, it looked like that was the only viable option.

Fortunately, times seem to be a changin’.  Calorie restriction studies in mice are far more than calorie restriction studies, something I discussed in my last blog you can read here.  This opens up a viable option that’s far easier to apply to your life than calorie restriction, far less restrictive, and may lead to comparable effects.  What I’m talking about is called time-restricted feeding and it seems to prevent the deleterious effects of a poor diet in mice.  The same type of poor diet that most of us eat every day.

Fundamental to the beneficial effects of time-restricted feeding are circadian rhythms.  For years we believed that circadian rhythms were controlled simply by light exposure.  We’ve recently learned that while light sets that master circadian clock in the brain, every one of our tissues and organs has their own peripheral clock that appears to be set by different cues such as the feeding/fasting cycle and glucocorticoids such as cortisol.

Taken from: http://www.endthistrend.com/wp-content/uploads/2013/10/Circadian-Rythms.png

Calorie restriction, circadian rhythms, and time-restricted feeding

In a recent blog, I covered one of the big mechanisms behind the way calorie restriction improves health and promotes longevity: Regulation of circadian rhythms.  In this study, researchers discovered a host of genes that lose their circadian rhythm in older mice who were overfed.

When these mice eat a calorie restricted diet they regain the appropriate rhythm in most of the genes that they lost when overfed.  One of the important pathways they regained is a pathway called autophagy.

Autophagy functions as a cellular housekeeping process that recycles damaged or unused cellular proteins for use elsewhere.  A recent study looking at factors that modulate longevity in the nematode worm C. elegans found autophagy to play a role, but not the role you would think.

Autophagy is critical to survival in young C. elegans because it’s a way to remove damaged proteins.  But with aging, autophagy gets mucked up somehow.  By blocking autophagy in older worms, researchers were able to increase longevity.  You would think that speeding up autophagy would be the plan to longevity, instead, something must go wrong with autophagy as we age.

Another hallmark of aging is the loss of circadian rhythms such that once robust rhythms become lost.  Perhaps it’s not that autophagy becomes dysfunctional with age, rather, it may be dysregulated with circadian timing being the critical factor.  As I covered in the blog above, calorie restriction was able to rescue the circadian rhythm of autophagy in older mice.  But, this could have also been due to time-restricted feeding as calorie restricted mice eat their food within 3 hours.

Fast forward to now, and another recent study identifies chromatin remodeling as a critical factor in the aging of yeast cells.  In this study, researchers found that too much or too little chromatin remodeling shortens lifespan.  Before I get ahead of myself, let’s cover chromatin remodeling and why it’s important.

Taken from: http://www.discoveryandinnovation.com/BIOL202/notes/images/Freeman_transcription1.jpg

What is chromatin remodeling?

Chromatin is a complex of DNA, RNA, and proteins such as histones that regulates how exposed DNA is.  Basically speaking, when a gene is turned on, it needs to be exposed so that the gene can be read and it’s protein synthesized.  However, if the gene is turned off, you don’t want it exposed because that can lead to DNA damage.

Think of chromatin like a book.  You can’t read a book if it’s closed, so you need to open it up to the specific page you want to read to get the information.  Now, imagine that it’s raining outside.  You don’t want to expose your pages to the weather so you want to keep the book closed until you absolutely need to or the rain has let up, otherwise you’ll damage your book.

Chromatin remodeling is the opening and closing of the tightly packed structure of DNA to allow genes to be expressed when they’re needed, but to prevent DNA from being exposed to potential damage when genes are turned off.  What this study shows is that there’s a Goldilocks effect to chromatin remodeling:  Too little prevents genes from being expressed in an optimal way while too much exposes your DNA to potential damage.  In other words, there’s a sweet spot for chromatin remodeling.  So why should you care?

Taken from: http://www.nature.com/nsmb/journal/v16/n5/images/nsmb.1595-F1.jpg

Chromatin remodeling and circadian rhythms

Circadian rhythms are natural variations in physiological processes that follow a 24 hour cycle.  They’re also regulated, in large part, via chromatin remodeling. But chromatin remodeling is also dependent on circadian rhythms.

Environmental factors such as light exposure, the feeding/fasting cycle, and physical activity alter our physiology by adjusting gene expression, which requires chromatin remodeling.  Additionally, chromatin remodeling is dependent on circadian metabolites such as nicotinic adenine dinucleotide(NAD+), acetyl CoA, and S-adenosylmethionine(SAM-e).

This interdependence can be both a blessing and a curse.  When we’re young and our circadian clocks are in sync with one another, we experience proper cell to cell communication, hormonal balance, and overall function.  Basically, we’re healthy and feel great.

But when we’re old or experience circadian disruption such as jet lag, everything is thrown out of balance.  This is likely why circadian disruption and/or aging increases our risk of chronic disease and death.  We’re sick and feel terrible.

Taken from: http://www.isciencemag.co.uk/wp-content/uploads/2014/12/circadian-rhythm-aging-oregon-14485…

Aging and circadian rhythms

There’s a fundamental difference between the young and old as it pertains to circadian rhythms.  It all boils down to the fact that we have a fairly robust rhythm no matter what we do when we’re young that seemingly fades as we age.  Why this happens we don’t necessarily know, but we do have an idea as to how we can fix it.

As we age, it becomes more and more important to expose ourselves to factors that sync our circadian clocks, called zeitgebers or timegivers.  The primary zeitgebers are light exposure, a proper feeding/fasting cycle and physical activity.  Other factors such as temperature, and social interaction can also help set the clock, as can certain pharmaceutical drugs.

My experience working with clients is that the first 3 are more than enough to sync your clocks and re-establish a robust rhythm.  Furthermore, most people are doing nothing in the way of looking at these factors from a time perspective.  A lot of us exercise and regulate our diet, few to none of us pay attention to how these factors are appropriately structured within the day, and no one really pays attention to light exposure.  This is a big problem because poor light exposure in the morning and too much light exposure at night(LAN) are all too common.

Taken from: http://www.frontiersin.org/files/Articles/120454/fgene-05-00455-HTML/image_m/fgene-05-00455-g001.jpg

Why focus on circadian rhythms?

Circadian rhythms play a central role in how our biology works at the systems and cellular level.  They regulate hormonal output, energy metabolism, cellular replication, and cell-to cell communication in powerful ways.  There’s a reason the 3 researchers who discovered the molecular machinery that runs the circadian clock won the Nobel prize in medicine this year.

If we look at circadian rhythms for what they appear to be, I’d say it’s absolutely essential to pay attention to them if your goal is to live a long and healthy life.  It’s no mistake that the Blue Zones are found in villages in the middle of nowhere and not apartment buildings in Queens; exposure to normal light/dark, active/rest, and feeding/fasting cycles are virtually thrust upon these people.

This brings us to why you should be focusing on your circadian rhythms if you care about hour health- and lifespan: It’s how your body’s supposed to run optimally.  Take something like autophagy, which doesn’t happen to a significant extent during the day in humans.

Nutrient availability is the primary driver of autophagy, with autophagy ramping up in the fasted state.  Part of this is scheduled maintenance, but another part is dictated by the need for nutrients.  Autophagy doesn’t just recycle busted cellular equipment, it also degrades proteins you don’t need in the cell so you can use them for energy.  Energy you need in a fasted state, whether it be an overnight fast or a prolonged fast.

So, what happens if we’re never in a truly fasted state?  Furthermore, what kind of an effect does the chronic caloric surplus and 15+ hour food orgy most people practice have on autophagy?  Given the regulation of autophagy by the circadian clock and the feeding/fasting cycle, and the recent study showing defective autophagy to be a potential driver of the death of neurons in neurodegenerative diseases, you may want to put circadian rhythms on your radar.

Now, you can add the role chromatin remodeling has on aging.  When we look at the bi-directional regulation between circadian rhythms and chromatin remodeling, we appear to be getting a pretty clear picture that healthy aging and longevity likely require you to pay attention to circadian rhythms.

Conclusions

The circadian clock exerts powerful control over our physiology.  While the circadian cycle is often only associated with the 24 hour day, it also sets up a clock that functions over a longer time period: the aging clock.  Damage you accumulate every day builds up over the course of many years, especially as you consider other factors such as cellular senescence and stem cell depletion.

It’s no mistake that every pathway currently under investigation as a means of promoting age rejuvenation or promoting longevity is in some way regulated by the circadian clock.  SIRT1/NAD+, mTOR, AMPK, and telomere length are all regulated by the clock, while SIRT1/NAD+ may actually be the metabolic arm of the circadian clock.  With all the data available, it appears as though circadian rhythms may be the forgotten factor in optimal healthspan and longevity.