My grandma is 101 years old this year. Her mind is completely lucid and except for high blood pressure, which is a chronic condition she has been diagnosed with for decades and is well under control with medication, she is in excellent health. Just a few years ago she was still hiking at such rapid pace I could hardly keep up with her. My three other grandparents have died, but they all lived to be over 90. So I have exceptionally good genes for longevity, and yet I look at my grandma and wonder: Do I really want to live that long?

Despite her extraordinary health, my grandma is quite limited in her daily activities. Other than daily walks around the neighborhood and occasional family gatherings, she hardly leaves the house. She lives with my parents and my uncle, who take good care of her. Her children, grandchildren, and even great grandchildren come to visit her at least a few times a year. They pay her respect, but a lot of times I feel like they treat her like a little kid, talking to her as if she could only understand kindergarten vocabulary. The conversations inevitably center around the past, reminiscing the good old times. When she is not engaged in family conversations, she watches TV or dozes off in her chair – she probably spends most of her waking hours in that chair half asleep. By all objective standards, she is enjoying her golden years… and yet I want more. If I live to be 100, I don’t want to be talked down to as if I were a little kid. As much as I enjoy family life, I also want independence, the freedom to go places by myself, experience new things, make new friends, and even learn new things. I don’t just want to talk about the past. I want to be fully engaged with the present, still active and productive, contributing in some way. I even want a future to look forward to at the age of 100. And by future I don’t mean death or some religious reincarnation. I mean actual hope that my life on earth in the next decade will be better than my previous 10 decades. I don’t just want longevity. I want vitality.

But is that possible? This is the subject of “Lifespan: Why we age – and why we don’t have to” by David Sinclair, professor at the Harvard Medical School. Having watched his vivacious grandma slowly wither away in the last 10 years of her life in a debilitating condition, Professor Sinclair dedicated his life to aging research, trying to figure out how we could cure the disease of “aging”. It wasn’t an easy read for me, given my limited high school knowledge of biology, and the fact that Professor Sinclair isn’t the best writer out there – much of the book is quite repetitive complaining over and over again that “aging” has not been treated like a disease and therefore not enough funding has been devoted to aging research, but the messages in the book are too important for me to ignore. So I trudged along.

And the result was eye opening. Professor Sinclair believes with the rapid advancement in medical and genetic technologies, it will soon become a norm for most people to have a “healthspan” of 120 years. Notice it is not lifespan, but healthspan, the part of a person’s life during which he/she is in good health. The evidence is compelling – just a hundred years ago, very few of our ancestors expected to live beyond 50. In fact, the Social Security program in the US, which was established in the 1930s, was designed in such a way that people would work for many years paying in taxes, but would not live long enough to collect benefits. Life expectancy at birth in 1930 was only 58 for men and 62 for women, and the retirement age was 65. But that plan has gone awry -- just in a few decades (a remarkably short period of time compared to the hundreds of thousands of years of human history), we have increased our average life expectancy to over 80, a 60% jump. As a result, the recipients of social security benefits in the US have surged from just over 6 million in the 1930s to over 40 million currently, jeopardizing the solvency of the program. And this is just the beginning. Professor Sinclair postulates that Moore’s Law, the trend that computing can dramatically increase power and decrease in relative cost at an exponential pace, does not only apply to digital innovation, but is also true for innovation in human evolution. We have just reached the critical point where the growth curve is about to explode.

The first step in the road to long healthspan is to pinpoint the fundamental reasons why we age. We have always accepted aging as a natural part of our lifecycle. But now scientists are challenging that assumption. Aging is a disease, Professor Sinclair boldly declares, and just like cancer or diabetes, there are molecular and cellular changes that lead to aging. Once we understand what these underlying causes, we should be able to find cures for “aging” just like how we conquered many other diseases like smallpox or HIV.

In recent years, scientists have already identified nine interconnected “hallmarks of aging”. Determined mainly by our genetics, but modulated by environmental factors, each of these nine hallmarks contributes to the damage that occurs with age and ultimately drives age-associated pathologies (wrinkles, gradual loss of muscles, vision, hearing, memory – all the fun things that come with aging):

·? ? ? genomic instability

·? ? ? telomere attrition

·? ? ? epigenetic alterations

·? ? ? loss of proteostasis

·? ? ? deregulated nutrient sensing

·? ? ? mitochondrial dysfunction

·? ? ? cellular senescence

·? ? ? stem cell exhaustion

·? ? ? altered intercellular communication

Yes, much of this is biology mumbo jumbo to me, but what I take away is scientists are starting to understand the mechanisms through which we age. If we can address one of these nine things, we can slow down aging. If we can address all of these, then we can all become Benjamin Button – except that we can stop the age reversal process at age 20 and stay there forever!

And here are some gems in the book I can make sense of –

1.? ? ? Pine trees can live for 5,000 years and their cells do not appear to undergo any decline in function as they age – scientists call this “negligible senescence”. Interestingly, half of their genes are close relatives of ours. In particular, scientists have discovered a gene in pine trees called FOXO3, which is also found in long living mammals like whales and in most centenarians across a variety of ethnic groups around the world. This is amazing to me for two reasons: 1) it brings a whole different level of understanding to the Zen spiritual saying “We are the universe and the universe is within us.” Yes, literally. How remarkable that all living creatures essentially share the same longevity gene! 2) If our close cousins in the universe have figured out how to live a long healthy life, we can as well – as long as we awaken the universe within us!

2.? ? ? A few molecules have shown promise as potential anti-aging recipes, at least in the lab. Resveratrol—a compound found in grapes, red wine and nuts— affects the activity of enzymes called sirtuins. Sirtuins control several biological pathways and are known to be involved in the aging process. By activating sirtuins, resveratrol stimulates our survival circuit and thereby extends healthspan in animals. Dr. Sinclair’s lab has demonstrated resveratrol-fed mice live 20% longer than mice without resveratrol. Now before you plunge into drinking red wine, it should be noted to get the same dose that was given to the mice, you would have to drink 1,000 glasses of wine every day. It turns out resveratrol isn’t very soluble in human gut. So we have not quite figured out how to replicate the longevity effect in humans, but it is proof STACs (sirtuin-activating compounds) can be a pathway to ant- aging.

In fact, there has been a flood of research on STACs in recent years. Another STAC is NAD. Without sufficient NAD, the sirtuins don’t work properly. But NAD levels decrease with age throughout the body, in the brain, muscle, skin, and immune cells. Professor Sinclair showed by boosting NAD in yeast, the yeast cells can live 50% longer. There seems to be at least two ways to boost NAD levels in humans: 1) via NR, a form of vitamin B, which is found in milk. 2) via NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. While studies that try to demonstrate the longevity effects of NR or NMN supplements are far from conclusive and Professor Sinclair explicitly disclaims that he is a researcher, not a medical doctor and does not endorse any supplements, it is noteworthy that he and his 80-year old father both have been taking NMN supplements and his father has been living an extremely active life with no sign of slowing down.

Finally, metformin, a cheap and effective drug to treat type 2 diabetes, may turn out to be a miracle drug. Studies have shown metformin can reduce the likelihood of dementia, cardiovascular disease, cancer, depression and even frailty. The way it works is metformin slows our cellular process to convert nutrients into energy, therefore activating an enzyme called AMPK, which in turn boosts NAD levels. Professor Sinclair is advocating that metformin should be prescribed not only to type 2 diabetes patients but to all people who experience aging symptoms.

3.? ? ? Professor Sinclair’s book was published in 2019, before the pandemic. Even so, he hailed the development of vaccine as one of the most seminal technology breakthroughs in human history that contributed to increased human lifespan. The last year and half have further illustrated his point. What if we have a vaccine against aging? It may not be as farfetched as it sounds. Cellular reprogramming, the process that allows jellyfish to regenerate, is possible through cloning and gene editing (Jennifer Doudna and Emmanuelle Charpentier just won last year’s Nobel Prize in Chemistry by developing the gene editing technique called CRISPR). There has already been some encouraging research to show reprogramming can reverse vision loss caused by glaucoma, an aging disease in the eye.

4.? ? ? If you cannot wait for the scientific community to come up with some miracle youth pill, there are some well known practices you can adopt to stay young and healthy. It turns out the secret is to not stay too comfortable. A bit of adversity or cellular stress is good for our epigenome because it activates AMPK, boosts NAD levels and activates the sirtuins, our survival circuit. These mildly stressful and stimulating practices include restricting calorie intake by doing intermittent fasting (either skipping a meal every day or eating less 2 days out of the week), exercising more, and braving the cold (by swimming in icy cold waters) and hot (by doing saunas) once in awhile.

How long do you want to live? For most people, the answer is not forever. The assumption is we age and inevitably with aging, our bodies decay, our qualities of life decline. Today, most people would be happy with 80 years of healthy life. But what if aging is a disease that is treatable? We have demonstrated humans are a species that is capable of defying the natural laws of evolution (we have grown our own food to solve for hunger, we have created a whole digital world to entertain ourselves, we have invented medicine and procedures that cured many diseases). We may have been given a body that is meant to last for only 50 years, but through our ingenuity and innovation, we are redefining the terms the universe has given us. What if it is possible to live to 120 or 150 without loss of quality of life? What if I have another 100 years to live? What if I don’t have to be like my grandma, spending most of her old age dozing off? What if we don’t have to slow down and plan for retirement (not because we cannot afford to retire, but because we don’t feel decrepit, we feel just as energetic as twenty-year-olds but with more wisdom and patience and we have more to give and learn)? In that case, I may want to live forever! Do you?