Lessons from: Age Later

Name: Age Later

Author(s): Barzilai, Nir

Synopsis

Ageing is a disease: If you think about it, for us to grow weaker as we grow older does not really make sense - it is something that we have just assumed as an immutable fact about life.

Till about our 25s or even 30s, things are on an upward trend, our bodies are generally getting faster, stronger, better at living. And then things start going slightly downhill (we may not even notice), and then they really start going noticeably downhill when we hit our 50s. Why?

Why are our bodies programmed to have a self-destruct button? Why are we born with this time bomb inside us?

The author writes: We have a hundred to thousandfold greater chance of dying from aging than of dying from other risks like obesity or high cholesterol.

Aging is so powerful that if you are a dedicated 80-year-old who does all their exercises, takes all meds and supplements, sleeps well, maintains hygiene, has good social connection and life purpose; you are still more likely to be dead the following year than a super obese twenty-something who does not exercise and spends all their time lazing around the house. Why?

Peter Attia writes: The short answer is that evolution doesn’t really care if we live that long. Natural selection has endowed us with genes that work beautifully to help us develop, reproduce, and then raise our offspring, and perhaps help raise our offspring’s offspring. Thus, most of us can coast into our fifth decade in relatively good shape. After that, however, things start to go sideways. The evolutionary reason for this is that after the age of reproduction, natural selection loses much of its force. Genes that prove unfavorable or even harmful in midlife and beyond are not weeded out because they have already been passed on. 

That, is actually a pretty good answer, according to me.

Anyway, what this book is - is basically a story about the authors experience with centenarians, people who live to 100 years of age and often beyond and are thus able to "age later", along with his experience with various stakeholders involved in the medical, geroscience and longevity field as he set up studies, experiments and companies to find out how this ageing thing works.

Let's see if there is something that mere mortals like me can take home.

Core ideas

Centenarian

noun [ C ], UK  /ˌsen.təˈneə.ri.ən/ US  /ˌsen.t̬əˈner.i.ən/

someone who is a 100 years old or more

1. SuperAgers: There are some people who "age later", You know them by the word "centenarian". Not only do they live longer, most of those years are also healthy and when they do die its fairly quick (squaring the mortality curve).  It's not that super agers don't get the main chronic diseases (ASCVD, disbetes, cancer, neurodegenerative disease), they just get them later, way later in life, like decades later. 
1. The reason they are able to do this is because of unique genetic makeup (there is no "one" perfect genetic configuration) that makes each individual centenarian live long. Also, this longevity tends to run in families.
2. Generally, centenarians:
1. Tend to have high levels of good cholesterol (HDL), as well as larger (in size) HDL and LDL particles
2. Tend to have unusually low levels of IGF-1
3. Tend to have unusually high levels of some mitochrondrial-derived peptides (MDPs)
3. It's not that centenarians have perfect genomes or that they lead super healthy lives (some of them do), but rather that they are protected from the consequences of ageing by parts of their own DNA (more specifically, variations/mutations in certain genes) - Yep, by virtue of being alive all of us have won the genetic lottery, but these folks seems to have won more.
1. The book goes into detail about what we know of these mutations and their effects, such as loss-of-function mutation in the CETP gene (increases HDL) and the APOC3 gene (increases HDL, lowers triglycerides), deletion of exon d3GHR (lowers IGF-1 production), variation in FOXO3 (improves metabolism, cardiovascular health).
2. Ageing for the rest of us: We age because, well, there are a few reasons (there may be more):
1. Genomic instability: DNA in our cells develops random mutations, these mutations are less likely to get fixed the older we are, leading to impaired cellular functioning that at large enough scale starts to impact organs. Telomere damage/shortening may be one of the reasons for these mutations.
2. Epigenetic damage: As we age, our cells lose information (become less adept at reading DNA) because epigenetic mechanisms scramble the information on the DNA, which leads to disease a general ability to function. Epigenetic factors like:
1. DNA methylation which is a process that activates or deactivates genes.
2. Histones package DNA into structural units and also play a role in gene regulation.
3. MiRNA (micro RNA) can silence other RNA thus prevent gene expression.
3. Cell senescence: Cells that refuse to die naturally (a process known as apoptosis) and instead linger around releasing inflammatory cytokines, which then start impacting the rest of the body negatively.
4. Mitochondrial dysfunction: As we age, our mitochondria suffer free radical damage and accumulate damage in their own DNA, which impairs their ability to produce ATP. Mitochondrial dysfunction is associated with a bunch of serious health issues.
5. Metabolic dysfunction: Our bodies become less efficient at converting food into energy.
6. Challenges in Proteostasis: The body becomes less efficient at clearing out misassembled proteins.
7. Immune dysfunction: Body become less efficient at fighting disease.
8. Inflammation: If inflammation is chronic then it contributes to ageing.
9. Antagonistic pleiotropy theory: Biological resources we need for reproduction when we are young may end up hurting us when we are old (like growth hormone and IGF-1).
3. Biological vs chronological clock
1. Chronological age is your age measured since the time you were born, simple.
2. Biological age, on the other hand, is supposed to be the "actual age" of your body basis what it can do and how well it works.
1. Broad consensus is still being formed on biomarker(s) of ageing that decisively reveal a person's biological age.
2. DNA methylation seems to be a leading candidate for predicting biological age. Look at this super cool image from Wikipedia that tries to explain how methylation alters gene expression (also look at the scale at which we are operating here):
1. 
3. BTW even different organs inside a person can have different biological ages.
4. The point is: you want to generally have a younger biological age.
3. How to slow our biological clocks:
1. Exercise your body and brain: Exercising, across any book I have read till date, is universal advice. Our bodies were built to move, so we should move them. Strength training, aerobic exercise and training for stability. Stay mentally sharp by learning new skills as you grow older.
2. Getting the right nutrition, not being over nourished: (this is a complex and often culturally intertwined topic, but generally) Eating in moderation, practicing some form of regular/daily (and occasionally longer) caloric restriction (esp. as we cross 25 years of age), getting the right macros (not too many carbs, but a good amount of fat and fiber), not being too lean (or course, not being fat either), hydrating well.
3. Supplement intelligently: Try not to experiment with too many nutraceuticals (depending on the country where you live, they may or may not be as strictly regulated as pharmaceutical drugs are), and take only that which you know you are deficient in. If you are young then it may be so that you are not deficient in anything and are able to effectively absorb everything from your food, as you get older you may want to get checked for the following: vitamin B12, vitamin D and calcium.
1. On a related note: Important to figure out what is going on in your body, so get tested for the usual markers depending on your age (like HbA1C, CRP, HDL/LDL etc.)
4. Sleep well: Get your 8 hours of sleep, design the right environment and routine around your sleep.
5. Have purpose: If you live for something bigger than yourself (your ego) then it is likely that you will live a happier and healthier life (I am not sure if this is causal, but it may be that people who have purpose tend to do less risky stuff because they fear it may compromise their ability to contribute to their purpose).
6. Be positive: Be easy-going, laugh often and optimistic. Don't bottle up your emotions too much. Try to have meaningful social connections. Life usually finds ways to challenge us, and having an overly paranoid, obsessive or pessimistic attitude is like adding fuel to the fire.
4. Preventing a looming world crisis?
1. The world is living longer but it is not living healthier, and this means more older people get added to the world's population each year. They need to be taken care of and may not be able to contribute to society and economy like they once were, and most importantly they live the last years of their lives in pain and disease - a fate no one wants.
2. This is unfortunate because older individuals generally have a wealth of experience and wisdom gained over a lifetime of making mistakes and learning what works - something that can be immensely valuable for younger generations.
3. The world's health adjusted life expectancy (HALE) trails its life expectancy. For example, in my home country of India, one can be reasonably expected to live 70-72 years, however, its HALE is between 50-59.9 years, which means that Indians are getting shortchanged a full decade of healthy living.
1. 
4. This is a key reason why longevity/healthspan R&D is crucial - The world is only going to live longer in the coming decades.
5. A pill for ageing?
1. Metformin: [When writing about the subject of health and longevity, I try not to discuss specific drugs or medicines, but I am making an exception for Metformin, which over the last decade has become a popular and promising "longevity" medicine.]
1. Indeed, the author thinks Metformin has great promise and talks at length about his plans to test it in his Targeting Ageing with Metformin (TAME) study. He also mentions that he takes Metformin.
2. Metformin is not new; it is an FDA-approved drug used successfully to treat diabetes for more than 60 years now.
3. Apart from being effective in managing diabetes, it has also been efficacious in ASCVD and cancer.
4. However, the real reason metformin is so important is that if TAME is successful, it may be the first drug that will be marketed as one that targets ageing. This is nothing short of revolutionary and has significant scientific, economic and cultural consequences. And future generations of drugs that are developed as a result may be even better at "fixing" ageing.
2. In the concluding chapter of the book the author talks about the more cutting-edge research and development that seek to stop and possibly reverse ageing. He talks about omics, personalized medicine, early detection, reversing cellular age, generic engineering and other pioneering explorations. He is hopeful that the drugs and other interventions that result from this research will keep most people healthy for an additional one or two decades and "the most common side effect will be living to one hundred and beyond".

Notable quotes

• Aging transforms us, remakes us, breaks us, destroys us. But why?
• By the mid - 1900s, human life span increased until the average reached eighty years, which is where we are now. But we start accumulating diseases after the age of sixty, and many people are being treated for three different diseases or chronic conditions by the age of seventy - five. So regarding the future of humanity and quality of life, it’s clear that finding a way to prevent or delay the onset of age - related illnesses is one of the most important mysteries we can solve.
• aging poses a dramatic increase in our risk of having every chronic disease.
• We experience old age and illness as one and the same thing, whether it’s diabetes or Alzheimer’s, Parkinson’s or cancer, but at seventy, the SuperAgers have twenty to thirty more mostly disease - free years ahead of them.
• That said, it’s important to clarify that centenarians’ bodies are not young. Many of them have some limitations like poor eyesight or hearing, some have less mobility than others, and arthritis is common. But the major diseases are delayed, and at the age of their retirement, many of them were not seeing a doctor and had no medical expenses.
• Demographers estimate that for most people , genetics are responsible for about 20 – 25 percent of aging and the environment is responsible for the rest. But the statistics are vastly different for centenarians, whose genes are about 75 – 80 percent responsible for how they age and the environment accounts for only about 20 percent.
• Evolution prioritizes reproduction, so that may be why the aging process picks up speed after reproduction.
• ... rapid aging is the price paid to achieve better reproduction.
• Abdominal obesity — think older people who are thin but have big bellies — is the marker for the onset of diseases.
• ... your body weight that has the biggest effect on your blood levels of cholesterol.
• “The important thing is to keep the brain going, you see”
• Morgan Levine, a pathologist at Yale; and a team of others have created what they call a “clock” that can predict the chronological age with just a few hundred methylation sites. This clock is a much better predictor than biological age , and there are companies already offering tests that use this innovation .
• I can tell you with certainty that growth hormones do not grow your life span.
• People who say that taking growth hormones makes them feel great are predominantly experiencing a placebo effect.
• Never put off your dreams.
• It really doesn’t matter what disease you have to begin with; your chances of getting any of the other diseases is the same because aging drives them all.
• Although functional decline is often caused by the burden of multiple diseases, in many other cases, the decline occurs without the presence of disease , suggesting that it’s simply a result of the aging process.
• For the first time ever, there are more people on earth who are older than sixty - five than people who are younger than five.
• Nobody wants to live to be one hundred if they are going to be sick for the last forty years.
• ... when I ask older people what’s on their wish list, at the very top is getting a job ... they want to be involved and contribute in whatever way they can.
• So to be clear, while there are scientists exploring immortality — and who can say whether they can achieve this goal or whether they should?
• Our maximum potential life span as a species is thought to be about 115 years, but many people die before the age of 80 after suffering from an average of three diseases. So we have 35 extra years that we can realize.
• Hands down, the most important intervention we have for aging is physical exercise, which has positive benefits for males and females at every stage of life.
• Based on the existing evidence, it appears that we’re meant to be physically active throughout our lives, but at some point between ages sixty and eighty, we start to lose energy and muscle strength as the biology of aging affects our whole bodies. Cardiovascular ability also declines with age, so strength training and cardiovascular exercises are particularly important as we get older. The key is to try a wide variety of activities and exercises that increase strength and bolster your cardiovascular system and to stick with the ones you like most.
• "If you have a reasonable life standard, if you are not in danger that you are going to lose it, and if you are not a dreamer, sit on your behind where you are. Don’t move. It’s not easy."
• While muscle mass loss is a concern, losing strength is a more significant problem.
• We start losing muscle mass at about the same age that we see an increase in type 2 diabetes. Muscle is our most important organ for maintaining our sensitivity to insulin, because muscle stores most of the body’s sugar as glycogen.
• ... paying attention to how much you eat and choosing to eat just a little less at each meal can make a big difference.
• ... safe to assume that a diet that’s 65 percent carbohydrates or more is not beneficial.
• ... lowest mortality rates are associated with people who probably have some extra subcutaneous fat, and this applies to men and women of all ages.
• Cold-pressed extra-virgin olive oil contains about thirty types of polyphenols that reduce inflammation and target the hallmarks of aging, particularly in the cardiovascular system and the brain. It also has lower acidity and tastes better than less healthy olive oils.
• Another way we can increase our chances for longer health spans and life spans is by taking steps to offset genetic mechanisms with lifestyle choices and — when they become available — new drugs that will be designed to specifically target those mechanisms
• ... what’s good for the heart often proves to be good for the brain, too.
• ... older people’s brains become biologically wiser.
• ... children who are in elementary school now will live long enough to meet their great - great - grandchildren.

In closing

It's a good book, an honest book, a hopeful book. Yes, it requires the reader to have a certain interest in the subject but it reads well, almost like a story and it seemed to me that the author was writing from the heart as he takes us through the book.

All well and good, but what do I care if some old folks have variations in their genes that allow them to live to a hundred? There were large parts of the book where I did not get any particular insight for this blog. Only when I got to chapter 8 is where the more practical advice for starts and it does not last for very long or is very specific. So this is not an instruction manual on how to live longer, its a observation log of those who actually do end up living longer.

Side note, I think its a little amusing to be alive at a time where we might be at the cusp of breakthrough, affordable, widespread and (hopefully) democratic increase in our lifespans and healthspans right at the time we are at also risk of making the world less habitable through climate change.