Why We Die

Author: Venki Ramakrishnan

Venki Ramakrishnan won the Nobel Prize in Chemistry in 2009 for his work on the structure and function of ribosomes. Ribosomes are a key component of our cells whose primary function is to synthesize proteins based on the genetic code carried in our DNA. Since this is an essential part of living, Venki knows a thing or two — or more accurately thousands of things — about what can go wrong in all the mechanisms that are crucial to sustaining our life. 

He writes very eloquently and quotes Hemingway from the “Sun also Rises” to say that we age “Gradually, then suddenly”. Over the course of our life we have a slow decline due to aging, followed by rapid changes that precede death. The book is filled with interesting little observations like this one about our risk of dying. At 25 years of age,  our risk of dying in the following year is about 0.1%. But then it rises to 1% at age 60 and is 16% by the time we reach the century mark. Co-incidentally I am close to 60 years old and my Mom just turned 100 this year!

Another interesting observation is that while the average age of mammals varies widely, they typically have roughly the same number of hearbeats over their lifetime. The number is about 1.5 billion. Humans had the same number until about a 100 years ago, but in the last century we have almost doubled our life expectancy and are now closer to 3 billion.

Venky has the ability to explain even complex discoveries in relatively simple terms and I learned a lot from reading this book. Here are a few key concepts that I am writing down mainly so I can remember them for later

Telomere shortening:

The DNA replication process is not able to accurately replicate the ends of the chromosomes. To prevent critical genes from being lost in the process, the ends of chromosomes have some genetic “padding” that is referred to as telomeres. These telomeres get gradually shortened as a result of successive DNA replication. It turns out there is an enzyme called Telomerase that can extend these telomeres and prevent them from getting shortened. However, these are limited to germ cells, stem cells and a few others. While it may seem tempting to use Telomerase in our general cell pool to reverse aging, we need to exercise caution as cancer cells often reactivate telomerase to enable continuous division. In fact some of the cancer treatments are to inhibit the telomerase activity in cancer cells to limit their ability to multiply.

Yamanaka factors:

While embryonic stem cells can grow into all the different organs in the body, mature cells become specialized and unable to take on other forms. In 2006, Professor Shinya Yamanaka discovered that mature cells can behave (replicate) like stems cells in the presence of four key protein transcription factors that are now referred to as Yamanaka factors. This groundbreaking discovery allows us to conduct all sorts of research with regular cells that we can now manipulate and even use to clone entirely new living beings.  From an aging perspective, we might be able to use Yamanaka factors to regenerate organs and reset the clock in their aging process. 

TOR (Target of Rapamycin):

Rapamycin was initially discovered by Suren Sehgal during an expedition to Easter Island in the 1960s. Early testing indicated that it was a good immunosuppressant and it had potential uses to improve the success of kidney transplants. mTOR or the mechanistic target of rapamycin is a crucial protein kinase involved in regulating cell growth, cell division and cell survival by integrating signals from nutrients, growth factors and cellular energy status. It’s name is derived from the fact that the drug rapamycin inhibits mTOR activity and thereby has significant implications for extending the lifespan of living beings. Dr. Peter Attia is a big fan of rapamycin and has written a lot about it in his book Outlive. However it’s full effects are not well understood and even he does not recommend taking it indiscriminately as a longevity drug. 

Metformin:

Metformin is a drug that is commonly used to treat type 2 diabetes. Metformin activates AMP-activate protein kinase (AMPK), an enzyme that plays a crucial role in maintaining cellular health. It also reduces oxidative stress which is another cause of cellular damage and aging. Metformin also has anti-inflammatory properties that can help mitigate one of the key contributors to age-related diseases. 

Caloric Restriction:

Similar to metformin, CR can lower inflammation and enhance mitochondrial health, contributing to better cellular health. Additionally, studies have shown that CR can influence DNA methylation patterns which are associated with biological aging. Dr. Steve Horvath developed an epigenetic biomarker of aging which is called Horvath’s clock that measures the pace of biological aging and predicts health outcomes for an individual. 

In summary, I learnt a lot but am not likely to do much with it.