Lifespan: why We Age and Why We Don't Have To

Summary

Central thesis is that aging can be explained by a unified theory called the Information Theory of Aging.

• While living longer is notable, prolonging the period of vitality is where meaningful change would occur in aging.
• The average lifetime has moved up overtime but the limit has not
• Argues that aging itself is a disease and a treatable one.
• What the author does to increase lifespan

Chapter 1

The survival circuit is the driver of aging. Sinclair elaborates on the current theories for biological aging. He goes on to argue that aging is multi-causal and defined by the hallmarks of aging.

Sinclair creates a digital / analog analogy for information storage within the cell. DNA is a digital, rigid encoding structure. The epigenome is an analog storage medium that responds to environmental conditions and can code for a wide range of states. To continue the analogy the epigenome degrades over time as a result of magnetic fields, cosmic rays, and oxygen.

There are stressors that will activate longevity genes without damaging them (hormesis). For example: intermittent fasting, low-protein diets, certain types of exercise, and exposure to hot and cold temperatures. This “right” amount of stress causes the cell to express the longevity genes and survive longer.

There are also hormeis-mimicking drug molecules that rally the longevity genes without causing any damage.

Chapter 2

• There isn’t an aging gene because we didn’t evolve to age. We have genes that impact the symptoms of aging. There are longevity genes that work against aging.
• Robert Mortimer and John Johnston worked with yeast in the 1950s realizing that yeast had extraordinary genetic and biochemical complexity, providing a useful model.
  • Discovered that mother and daughter yeast cells can have vastly different lifespans.
• Yeast genome was sequenced in 1992.
• Slow growth Supressor 1 (SGS1) is responsible for preventing a similar state to Werner Syndrome in yeast. Sinclair demonstrated that aging symptoms resulting in early death in yeast could be induced by swapping a mutated SGS1 gene.
  • Aged yeast cells nucleolus looked as if it had exploded.
  • The damage to nucleolus causes Sir2 protein to move away from the mating genes and into the nucleolus. This is a “gene B” mechanism.
    • When the siturins leave the mating genes (the “gene A” types that control fertility and reproduction), the mutant cells turned on both male and female genes, losing sxual identity as old cells do.
  • Sir2 prevents acetyls from accumulating on histones, which prevents the DNA from unpacking. By having some DNA packed vs. unpacked changes what is expressed. Genes are in euchromatin when they can be expressed where as genes in heterochromatin cannot be expressed. This is one pathway for the epigenome.
  • In the Wener mutants, ribosomal DNA (rDNA) was unpacking and creating “loops” within Southern blots termed extrachromosomal ribosomal DNA (ERCs). ERCs were also present in normally aged cells.
  • In a 1997 Cell article, Sinclair’s lab showed that adding ERCs to a young cell causes them to go sterile and die.
  • Adding an extra SIR2 gene increased yeast cell’s lifespan by ECRs
  • Aging and sterility in yeast appears to be caused by instability of the genome.
• DNA is not destiny, the epigenome determines how the DNA is expressed and when.
  • Identical twin studies place the influence of genetics at 10 and 25 percent on longevity
• Sinclair demonstrated that the epigenome plays be involved in aging by damaging DNA in mice without damaging other functionality. When tamoxifin was administered to mice, it induced expression of a gene that damaged the genome. The control group was otherwise normal. Expression of this genome damage caused aging in the mice. This removed other likely culprits of aging (e.g. radiation) while implicating the epigenome.
• Organisms with abnormal longevity:
  • The Bristlecone pine
  • The freshwater polyp Hydra vulgaris
  • Greenland shark, Somniosus microcephalus
  • Bowheaded whale, Balena mysticetus
• Waddington landscape, conceived of as embryonic cells (stem), represented by marbles roll down the hill of cellular differentiation into valleys that define their type (bone/muscle/organs/skin). In the information theory of aging, epigenetic noise causes the cells to lose identity and move towards adjacent valleys causing dysfunction and senescence (zombie-like cells).

Chapter 3

• “Law of Human Mortality” - by Bengamin Gompertz (1825) attempted to provide a mathematical description of aging by ascribing it two causes: chance without previous disposition to death and deterioration. The first part is a first-order rate reaction and the second part is an exponential increase in probability of death over time.
  • In yeast, the chance piece is the formation of rDNA circles and the exponential clock is the replication and exponential increase in those circles.
• Survival of a disease is well predicted by age.
• Wounds heal more slowly with age
• Tests of age:
  • number of push ups you can do, over 45 and 20 push ups you are doing well
  • sitting-rising test (SRT): sit on the floor barefooted with legs crossed, lean forward quickly and see if you can get up in one move
• Modern medical culture focuses on treating individual medical problems one by one, however age is a risk factor for all of them. Sinclair believes that age is a treatable disease that we can treat within our lifetimes.
• Disability adjusted life year (DALY) measures the years of life lost from both premature death and poor state of health

Chapter 4

• Blue Zone¹ diets (“longevity diets”) were those of residents of areas with particularly long lifespans: Okinawa, Japan; Nicoya, Costa Rica; and Sardinia, Italy.

Things that can be done now to increase lifespan:

• Eat less. Fasting creates adversity which causes cells to engage the survival circuit.
  • Cells few with lower doses of glucose live longer
  • The biosphere experiment gave a natural test of what happens when humans have enough food to avoid malnutrition while still being frequently hungry. After two years, all participants had improved body mass, BP, blood sugar and cholestrol
  • Fasting periods have been observed in some Blue Zon regions
• Intermittent fasting has shown to lower IGF-1 levels, reduce body fat, lower BP
  • 16:8 hour pattern
  • 75% fewer calories on 2 of 7 days
  • Eat Stop Eat
• Plant Based Diet
  • Amino Acid cause mTOR activation, lowering meat and diary intake may inhibit this pathway
  • Leucine in high levels may prevent the mTOR pathway from providing longevity benefits
• Exercise
  • Raises NAD levels
  • Longevity regulators head in the right direction (AMPK, mTOR, and siturins)
  • HIIT enanges the greatest number of health-promoting genes and more of them in older exercisers
• Temperature
  • Exposing your body to less than comfortable temperatures is an effective way to turn on longevity genes
  • Siturins are switched on by cold which activates productive brown fat in our back and shoulders
    • Brown fat is enhanced in mice with long lifespans
  • Exercising in the cold in particular appears to turbocharge the creation of brown fat
  • In cells that are on the hot side, NAD production is boosted, Sir2 works harder and the cells live longer. Similar mechanism to calroie restriction.
  • Heat seems to be less potent for longevity than cold.
• Prevent DNA damage
  • No Smoking, limit UV exposure, X-Rays, radon.

TODO Chapter 5

TODO Chapter 6

Chapter 7

• CAR T-cells are removed from the patient and then a gene is inserted to bind the tumor. T-cells are grown in mass and then given to the patient.
• Checkpoint blockade theory block the ability of cancer cells to present as regular cells
• Drugs can be checked against the patients genome for interactions.
• “xenotransplantation” is the idea of transplanting organs grown in one species into another. Luhan Yang found a way to eliminate retorviral genes from pigs that lowers the barrier to transplanting them.

TODO Chapter 8

Chapter 9

• Aging should be defined as a disease, and the first country to do so will have a leg up on the advances of aging. This will open up public funding.
• Must address consumption with innovation.
• Labor will change as people live longer, retirement and age will no longer be intertwined.
• Longer lifespans should promote interconnections amongst generations and increased responsibility to care for the future generations and the health of our planet.

Conclusion

• On June 18th, 2018, in the ICD-11, the WHO created a diagnosis code for aging (MG2A):

MG2A Old age • old age without mention of psychosis • senescence without mention of psychosis • senile debility

References