Strong disclaimer: My knowledge on biology is very limited. What I write below is based on my understanding from reading the book and I may have misunderstood or misinterpreted some concepts. All mistakes are mine

I learned lots of new things reading this book.

  • Theory of antagonistic pleiotropy - Genes that are beneficial in early life can have detrimental effects in later life.
  • Relationship between size, heart rate, lifespan to metabolic rate. Kleiber’s law states that metabolic rate scales to the 3/4 power of body mass. Natural limit of life span is roughly 120 years for humans.
  • Genes: Units of information that contain information on not only how to reproduce an organism and pass on its traits but on how to build an entire organism from a single cell and keep it functioning. Genes reside in our DNA. The information around DNA and RNA in chapter 3 “Destroying the master controller” is fascinating.
  • Proteins: Genes contain information on how to make protein. These are the workhorses of the cell. They regulate flow of molecules in and out of cells, catalyze chemical reactions, provide structure to cells and tissues, and perform many other functions. Our nervous system depends on proteins to transmit nerve signals and store memories. Antibodies are made of proteins. Ribosomes carry out complex process of reading mRAN to synthesize proteins. There are mistakes in this process too. Sometimes mRNA contains mistakes or sometimes ribosomes misreads it.
  • Protein folding: Proteins are made up of long chains of amino acids. These chains fold into specific three-dimensional shapes that determine their function. Misfolded proteins can lead to diseases such as Alzheimer’s and Parkinson’s.
  • DNA evolved from RNA as a way to store genetic information stably. Thousands of changes are inflicted on DNA in each of our cells every single day. Cell division is like copying a text three billion long where an error occurs sometimes there’s mistake in copying when cell divides. There is repair mechanism in the body to fix damage to DNA. I found this mind boggling.
  • Cells have limit on how many times they can divide. This is called Hayflick limit. Cancer cells are exception to this limit. I don’t understand how cells stop dividing. Why do chromosomes shorten with each division and role of telomeres.
  • Recycling the cell’s garbage - The process by which cells are destroyed and recycled. As we age, this machinery becomes less effective. Proteins that are incorrectly made or misfolded need to be indentified. Cells have a complex machinery to detect the buildup of these proteins and destroy them. Autophagy is used to ensure cells develop normally and get rid of defective proteins or aging structures. This is detailed in chapter 5 “Recycling the garbage”.
  • Alzheimer’s is caused by cell’s inability to manage excess of unfolded proteins. This in turn is caused by damage to control systems that manage quality control and recycling machinery of the cell. The damage to this machinery is caused by aging. A stupid question: Why can’t we create an artificial garbage disposal system to clear these misfolded proteins?
  • Caloric restriction (CR) - Reducing calorie intake without malnutrition has been shown to extend lifespan in various organisms. This is discussed in chapter 7 “Less is more”. This chapter introduces TOR and how it’s connected to CR and how inhibiting TOR can enhance health. TOR is helpful in early life for growth but it is unable to switch itself off when growth becomes excessive leading to cell deterioration and aging-related diseases.
  • Chapter 8 discusses the IGF-1 pathway and NAD and their role in aging. IGF-1 pathway and TOR pathway are connected in complex way. Inhibiting IGF-1 pathway has been shown to extend lifespan in various organisms. Metaformin, a diabetes treatment drug is thought to work by inhibiting IGF-1 pathway. How this drug works in not entirely clear. NAD is a molecule that is involved in energy metabolism and DNA repair. NAD levels decline with age, and boosting NAD levels has been shown to improve health and extend lifespan in various organisms.
  • Mitochondria: Gaia hypothesis. The powerhouse of the cell. I like the parallels drawn between how electricity is produced and exchanged in modern world through different ways. Mitochondria works similarly where it takes versatile forms of energy and converts them into universal energy currency of the cell, ATP. When cells need energy, it breaks the ATP bonds and use the energy released for any particular process in the cell. Mitochondria have their own DNA and can replicate independently of the cell. Mitochondrial dysfunction is thought to contribute to aging and age-related diseases.

When we digest the food, especially carbohydrates, we are effectively burning the sugar that we obtain by breaking down the carbohydrates … Sugar combines with oxygen and releases carbon dioxide and water and releases energy in the process. That is exactly what we do when we breathe in and out. The energy released during respiration is used by the mitochondria to produce ATP. We inherit our mitochondria exclusively from our mothers… diseases due to defects in the mitochondrial genome are inherited entirely from the mother. As we age our mitochondria still work but they have accumulated the defects. Not only do they produce energy less effectively, but they have becomes creakier and less effective at their myriad other tasks.

  • Senescent cells are produce in response to injury to promote healing and tissue regeneration. The same secretions signal to immune system to clear the senescent cells after healing is done. As we age, senescent cells accumulate in tissues and contribute to aging-related diseases. Senolytics are drugs that target and destroy senescent cells. This is discussed in chapter 10 “Aches, Pain and Vampire Blood”.
  • Human body replaces itself every seven years. Stem cells are responsible for regenerating tissues and organs. As we age, the number and function of stem cells decline leading to reduced tissue regeneration. Stem cell therapies are being developed to rejuvenate tissues and organs.
  • Fundamental problem with aging research is how to tell if their treatments is working. Standard practice would be to carry out randomized clinical trials. But aging is a slow process and it would take decades to see if a treatment is effective. Researchers are trying to identify biomarkers of aging that can be used to measure the effectiveness of treatments in shorter time frames.
  • Consequences of life extension - greater inequality, overpopulation. And second order effects of these. The consequences of increasing life expectancy on working beyond eighties as most of the population demography shifts from working to elderly. Smaller fraction of younger people to support an increasing cohort of older people in retirement. Relationship between age and productivity is complex.
  • Different parallels are drawn from various fields such as literature, business, and academia where best work is produced when they are young up to ages of forties. Old have advantage due to imbalance in the power as they have accumulated a great deal of wealth, reputation and powerful network of connections over time.
  • Ageism sits as it’s own category alongside racism and sexism these days.

Broadly five major themes around death and aging are covered in the book:

Drugs that mimic caloric restriction

  1. Through targeting TOR such as rapamycin and similar drugs
  2. Antidiabetic drug such as metaformin whose mechanism is not fully understood
  3. NAD boosters such as NMN and NR that help in mitochondrial function
  4. Senolytics - drugs that target senescent cells which are source of immflammation
  5. Stem cell therapies to rejuvenate tissues

TOR

Cells require nutrients to grow and divide. When nutrients are abundant, cells grow and divide rapidly. When nutrients are scarce, cells slow down their growth and division. This is regulated by a protein called TOR (Target of Rapamycin). When TOR is active, cells grow and divide rapidly. When TOR is inactive, cells slow down their growth and division. TOR is connected to caloric restriction (CR) because when nutrients are scarce, TOR is inactive. When TOR is inactive, cells enter a state called autophagy, where they recycle their own components to survive. Autophagy is thought to be beneficial for health and longevity because it helps to remove damaged cells and proteins from the body.

The experiments on mice showed improvements in both health and life span. It also delayed the on-set age-related diseases as it increased autophagy and prevented accumulation of misfolded proteins.

A problem with laboratory animals …. they are kept in highly protected and relatively sterile environment that does not mimic real-life conditions.

A long term rapamycin increases risk of infection and a mouse study in 2009 was stopped to avoid the possible suppression of immune response by rapamycin.

This is discussed at length in chapter 7 “Less is More”. I liked the history on how this promising compound was discovered named after Rapa Nui, the indigenous name for Easter island, how it nearly died in a scientist’s freezer and the whole story around persistence and luck.

Senescent cells

There are some cells that have stopped dividing but do not die. These are called senescent cells. These cells secrete inflammatory molecules that can damage surrounding tissues and contribute to aging-related diseases. Senolytics are drugs that target and destroy senescent cells.

Stem cells

There are some cells that have reached a final state - terminally differentiated - and will carry out their assigned tasks until they die. There are highly specialized cells for producing new cells to regenerate aging tissues. These are stem cells. As we age, the number and function of these stem cells decline leading to reduced tissue regeneration.

Some of the interesting quotes and lines from the book:

The immortality merchants of today – the researchers who propose trying to extend life indefinitely and the billionaires who fund them – are really a modern take on the prophets of old, promising a long life largely free of the fear of encroaching old age and death.

Why does death even exist? Why don’t we simply live forever?

… death is the price we pay for sex!

Death, in the inevitable sense … is result of aging. The simplest way to think of aging is that it is the accumulation of chemical damage to our molecules and cells over time.

Most people do not fear death so much as the prolonged debilitation that precedes it.

Consuming lots of calories allows us to grow fast and reproduce more at a younger age, but it comes at the cost of accelerated disease and death later on.

The anti-aging industry would love to produce a pill that can mimic the effects of CR without our having to forego the ice cream and blueberry pie.

Certain cells are programmed to die at precise stages of development. Scientists went on to identify the genes that sent these cells to commit suicide at just the right time in order for the organism to develop.

A simple corrective - restricting our calories and eating well - can do much to slow this deterioration through complex interconnected pathways. Much excitement in aging research is about prospects of producing drugs that inhibit these pathways and produce the benefits of caloric restrictions.

… not a shred of credible evidence that human cryogenics will ever work.

(Talking about tech billionaires) When they were young, they wanted to be rich, and now that they are rich, they want to be young.