• Sirtuins are a class of proteins that protect organisms from deterioration and disease by regulating gene expression (turning genes on/off)
  • Sirtuins need NAD+ to function properly
• As we get older, our NAD+ levels drop
  • By the time you’re 50, your NAD levels are about half what they were when you were 20
  • “You could argue NAD+ is the most important molecule in the body, maybe with the exception of ATP. But without either of them, you’re dead in about 30 seconds.” – David Sinclair
• NR and NMN are NAD+ precursors you can supplement with – both have been shown to raise NAD+ levels
  • You can also raise NAD+ levels with fasting and exercise 
• If sirtuins are the car, and NAD+ is the fuel, resveratrol is the accelerator pedal
  • Resveratrol also seems to improve cardiovascular health as well as stimulate autophagy pathways
• The primary cause of aging is a loss of epigenetic information (the pattern to which genes are turned on/off)

David A. Sinclair, PhD, is a professor in the Department of Genetics at Harvard Medical School and co-director of the Paul F. Glenn Center for the Biological Mechanisms of Aging. He is the co-founder of the journal Aging, where he serves as co-chief editor.

Dr. Sinclair's work focuses on understanding the mechanisms that drive human aging and identifying ways to slow or reverse aging's effects. In particular, he has examined the role of sirtuins in disease and aging, with special emphasis on how sirtuin activity is modulated by compounds produced by the body as well as those consumed in the diet, such as resveratrol. His work has implications for human metabolism, mitochondrial and neurological health, and cancer.

In this episode, we discuss...

• 00:17:59 - How caloric restriction, fasting, and exercise increase levels of a molecule called NAD+ and how this activates sirtuins, a family of genes involved in longevity.
• 00:21:47 - How NAD+ levels and sirtuin activities decrease with age, and how animal studies suggest that raising cellular NAD+ levels can trick the body into thinking it is younger.
• 00:23:03 - How resveratrol enhances the binding of sirtuins to NAD+ thus making sirtuins more easily activated for a longer period.
• 00:27:36 - We also discuss Steve Horvath's epigenetic aging clock, which measures DNA methylation groups, and how they may play a role in widespread gene regulation, including sirtuin genes, and how NAD+ may participate in resetting the clock.
• 00:31:54 - How the signal that resets the epigenetic clock in mice involves the Yamanaka factors -- a group of four transcription factors that can reprogram an adult cell to become a pluripotent stem cell that can form any cell type.
• 00:46:48 - How resveratrol is a xenohormetic compound and is produced when grape plants are stressed either in response to fungus or lack of water.
• 00:55:35 - How a phase 2 clinical trial involving people with Alzheimer's disease showed resveratrol improved cognitive function, improved cerebrospinal fluid amyloid beta levels, lowered markers of activated microglia, and more.
• 00:58:03 - How both nicotinamide riboside and nicotinamide mononucleotide have been shown to improve cognitive function and brain pathology in mice that have been engineered to get a disease similar to Alzheimer's disease.
• 01:06:19 - How older mice that were given nicotinamide mononucleotide experienced delayed aging in the liver, muscle, immune cells, eyes, and bones, but those that took a lower dose had improved mitochondrial function and enhanced physical performance.
• 01:01:22 - How there may be challenges in translating animal studies on nicotinamide riboside and nicotinamide mononucleotide to humans particularly due to the need to determine the dose required to promote health benefits.
• And so much more!

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• External achievements never create lasting happiness 
  • Sadly, the best way to internalize this is actually to obtain those achievements 
• We were put on Earth to live our life to the fullest – fulfill your desires, collect new experiences, and try new things (just don’t go crazy)
• Open relationships are HARD
• The pillars of a good life:
  • Take care of your body
  • Lean into discomfort
  • Cultivate and maintain a healthy community
• Quotes to ponder:
  • “Truth is love. Tell the truth and loving everyone is the same thing. You can’t love someone without telling them the truth.'”– Aubrey Marcus
    • “Our purpose here is to wake up to the truth of who we are, and all of the truth around us… If we’re all here to wake up to that truth, and we’re shielding that truth from somebody, we’re doing them a great disservice.”
  • “In a healthy relationship, instead of serving someone from your cup, you actually serve them from the overflow that fills the saucer around the cup. That way, no one’s ever drinking from their own cup of love, resources, or energy.” – Aubrey Marcus

Aubrey Marcus is a podcaster, author and CEO.

I wanted to find out how Aubrey defines living a good life, and how he structures his world to ensure that he's pointing in the right direction... As you might be able to guess, this episode is jam packed with amazing stuff.

Aubrey is someone who contemplates the finer elements of exactly how to make his mind and body a little better every day. Enjoy this insight into the life of someone who is unashamedly working to uncover all his weaknesses and turn them into strengths.

This episode is brought to you by The Protein Works. Head to https://bit.ly/TPWChrisWillx to check out their awesome range.

Extra Stuff:

Follow Aubrey on Instagram - https://www.instagram.com/aubreymarcus

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Get in touch. Join the discussion with me and other like minded listeners in the episode comments on the MW YouTube Channel or message me...

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• Systems > Goals – here’s why:
  • Committing to completing a specific goal often blinds you to other opportunities
  • With a goal, you feel as if you’re in a continuous state of failure until you achieve it
• Put yourself in situations where luck finds you
• “The best way to learn how to do something is to do it wrong”– Scott Adams
  • “If you do something wrong in front of other people and they know how you shouldn’t have done it, they’re going to tell you, and they won’t charge you for it. You can get all the free advice you want by doing bad work in public.”
• “If you’re creating art of any kind… if it doesn’t move somebody’s body, you’re not done yet”– Scott Adams
• Don’t force your creations
  • “I don’t try to create anything that I have to push. If I feel myself pushing or forcing it, I know it’s not going to work.” – Scott Adams
• Create things that you’re pulled too 
  • “If you can find an idea that pulls you, then all of the energy you’d normally have to muster on your own to put into it is unnecessary. The project actually gives you energy. It’s feeding you at the same time you’re building it.” – Scott Adams
• Turn your ego (which is usually your enemy) into a tool by dialing it up when confidence is needed, and dialing it down when it serves as a distraction
• Become aware of your blind spots by exposing yourself to concepts from a variety of different fields (psychology, history, economics, etc.)

Scott Adams is the creator of Dilbert, one of the most popular comic strips of all time. In addition to creating Dilbert Scott has been a Bestselling author and successful entrepreneur.

His many bestsellers include The Dilbert Principle, and How To Fail At Almost Everything And Still Win Big and his newest book Loserthink. For long time listeners of the show you know how big of a fan Sean is of Scott and on this episode they cover some his favorite topics such as Systems over goals, talent stacking and Scott’s creative process. If you want to learn how to win big in life this episode is for you!

Get the Latest from Sean right here – https://bit.ly/2RH3eaD

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• The chiliPAD is a mattress topper that circulates temperature-controlled water (varying between 55-110 °F), allowing you to optimize your sleep environment
• The OOLER is Chili’s follow-up product
  • The main difference? It’s app-controlled, allowing you to set a schedule that changes the temperature throughout the night.
• Your brain needs to drop its temperature 2-3 °F in order to sleep
• When you sleep in colder environments (with something like the chiliPAD) you get more deep sleep
  • This is useful, as deep sleep tends to decline with age

"The most exciting new podcast in the startup world.” - Eric Ries, Founder, and NYTimes bestselling author

Today's episode was actually a live recording with a good friend, a former investor and a continual mentor to me (and dozens of entrepreneurs who I also love and respect). His name is Justin Kan, and he was episode number one for Below The Line.

Justin is a founder and investor based in San Francisco. He has been building startups for close to 15 years now, and he's seen pretty much everything there is to see when it comes to the founder’s journey.

He's also a former partner at Y Combinator and has invested in dozens of companies, giving him a unique perspective on both sides of the table.

He is the co-founder and CEO of Atrium, a full-service corporate law firm that uses modern technology to serve startups all around the world in a fast, transparent and price predictable way. It's phenomenally useful. I've used it and so has a number of founders that have been on the podcast.

You can email James questions directly at [email protected] or follow us on Twitter @ twitter.com/gobelowtheline — “Below the Line with James Beshara" is brought to you by Straight Up Podcasts LLC

• Follow your intuition (your compass)
  • You don’t need to have all the answers, you just need to know which direction to go towards
• Every great business or creative project starts from nothing
• The root of success lies in showing up EVERY day to do the work
• Everyone has fear – don’t try to make it go away, just figure out a place to put it while you’re doing your work
• “All you have to do in order to be the noun is do the verb” – Chase Jarvis
• “If you don’t feel like an impostor, I don’t think you’re working hard enough” – Seth Godin

Super pumped for this week's podcast... If you happened to miss yours truly + Seth Godin on my tour stop in New York a few weeks ago, here it is.

Of course, the title "Creator Therapy" is a little tongue and cheek. Seth and I gathered with about 120 other creators for a conversation on creativity, creative blocks, and taking that next step. Seth is a sage as always. Super grateful to share the stage and soak in some of his wisdom.

Hope you enjoy the conversation, and please be sure to give a shout out to Seth on the socials if you received some value.

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