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Biology has made revolutionary advances in understanding genes over the past 100+ years, including recent research on the fundamental causes of aging and prospects for extending lifespan.
Demographic trends of an aging population are driving huge efforts to understand aging and mitigate its effects through research. Over 300,000 aging-related studies have been published in the last 10 years alone.
Some scientists claim we may be able to extend lifespans significantly or indefinitely through scientific advances, but others question if that is achievable or desirable. There are also ethics questions around access and societal impacts.
The author’s own career focused on how proteins are made in cells, which relates deeply to aging processes. He provides a broad and objective look at the current understanding of aging and debates, drawing from conversations with leading scientists.
Aging is intricately connected to many biological processes, so the book explores these from genes to cells to tissues and mortality. It examines why longevity varies across species and evaluates anti-aging research claims.
The first chapter frames aging and death at multiple levels from cells to societies, noting the complex organization and coordination within living things that ultimately face mortality over time.

So in summary, it overviews the huge momentum in aging research, debates around extending lifespans, the author’s goal for an impartial perspective, and how aging links to broader biology which the book will explore.

Organs and limbs can be transplanted between bodies if done quickly enough. The recipient’s bacteria and cells continue functioning normally.
Death occurs when the collection of cells that make up the body stop functioning together as a coherent whole, due to aging and accumulated chemical damage over time.
The precise moments of birth and death are ill-defined. Various events like fertilization, implantation, development of organs happen over windows of time.
Life exists on a scale from molecules to societies. Entities die when their component parts stop allowing the organic whole to function, similar to how cells die and cause individual death.
Longevity increases with organizational scale - cells die frequently but are replaced, while societies tend to outlive individuals and companies.
Information to continue life resides in our genes, which are passed from cells to offspring. This continuity of genetic information is what allows life to persist across generations despite individual death.
The theories of Lamarck and Darwin proposed different mechanisms for evolution - Lamarck suggested acquired traits could be inherited while Darwin proposed natural selection of inherited variations. Their joint 1858 presentation, along with Wallace’s independent proposal, helped establish the theory of evolution by natural selection.
In 1892, German biologist August Weismann posited a rebuttal to Lamarck’s ideas of inheritance of acquired traits. Weismann proposed the separation between germline cells (eggs and sperm) and somatic cells. Germline cells pass on genetic information between generations but are not affected by an organism’s experiences or traits. This is known as the Weismann barrier.
In the early 20th century, scientists J.B.S. Haldane and Ronald Fisher put forth theories to explain the evolution of aging and death. They proposed that genes which are harmful later in life can still be passed on if they are beneficial earlier.
British biologist Peter Medawar expanded on this with the mutation accumulation theory - harmful late-life mutations accumulate in the genome because natural selection no longer acts against them.
George Williams suggested antagonistic pleiotropy - some genes benefit early life but are detrimental later due to opposite effects at different ages.
Thomas Kirkwood’s disposable soma hypothesis is that organisms must allocate limited resources between early growth/reproduction and longevity/repair, leading to evolutionary tradeoffs that result in aging.
Experiments on model organisms provide evidence supporting these theories, showing aging tracks predicted patterns of mutation accumulation and antagonistic pleiotropy effects.
Mutations that increase life span tend to reduce fecundity (ability to reproduce), and caloric restriction also increases lifespan while reducing fecundity. This suggests a tradeoff between longevity and reproduction.
A study of British aristocrats found that among women who survived past 60, those with fewer children tended to live the longest, providing human evidence for an inverse relationship between reproductive output and longevity.
Menopause is unique to humans and some other species. Most females can reproduce until the end of their lives, whereas human females stop in midlife. This seems disadvantageous from an evolutionary perspective of passing on genes.
Existing theories propose that menopause may have evolved to 1) protect older mothers from risks of childbirth, allowing them to care for existing children into adulthood, or 2) allow grandmothers to help care for grandchildren, improving survival of genes passed down. However, these theories are debated.
Factors like the fixed number of eggs a female is born with matching average lifespan in the wild, or avoiding intergenerational conflicts, have also been proposed to explain menopause. More research is needed to understand its evolutionary origins.
The lifespan of mammals tends to increase with body size, following scaling laws related to metabolism. Larger mammals have lower metabolic rates and tend to live longer.
Within mammals, there is still considerable variation in lifespan. Some small fish live just months, while bowhead whales can live over 200 years. Steven Austad studies animals that deviate significantly from scaling laws.
Scaling laws predict that metabolism and lifespan are limited by size and energetic constraints. Geoffrey West uses scaling laws to estimate traits like lifespan, food intake, and heartbeats across sizes of mammals.
Exceptions like hydra and jellyfish that can regenerate call into question theories of unavoidable aging. Biologists focus on outliers to study mechanisms, not just average trends.
Austad discovered that lifespan scaling breaks down below 1kg, and defined a “longevity quotient” to identify outliers living much longer/shorter than expected. Naked mole rats and bats outperform humans on this measure.
While mice and rats are commonly used models, Austad questions this given their close adherence to scaling laws and relatively short lifespans compared to outliers worth further study. Understanding universal mechanisms could still apply to human aging.
The article discusses several unusually long-lived animal species like giant tortoises that can live over 200 years. Determining their exact ages and life spans is difficult.
Other long-lived species mentioned include turtles, Greenland sharks, bowhead whales, and a cockatoo species that can live over 80 years.
The relationship between mortality and age, known as Gompertz’s law, seems to be violated in some species that show negligible senescence (constant mortality rates rather than increasing with age). However, they still show signs of aging physically.
Bats and naked mole rats also vastly outlive other mammals of similar size. Factors like flight ability, hibernation, eusocial behaviors, and cancer resistance may contribute to their longevity. Naked mole rats in particular have generated interest as they seem resistant to cancer and aging.
However, all species discussed still age physically and their mortality does increase over time, even if more slowly than predicted. The article concludes by shifting focus to understanding human aging and longevity.
Life expectancy has greatly increased over the past century due to public health improvements like sanitation, vaccines, antibiotics, and fertilizers rather than medical advances. These factors reduced infant and child mortality.
While average life expectancy continues to rise slightly and is over 80 in some countries, there is debate around whether the maximum human lifespan has a fixed limit or is elastic.
Studies pointing to a limit cite statistical analysis showing dramatic reductions in all causes of death would be needed to significantly increase lifespans beyond 85 years. Biology also likely constrains aging rates.
However, others argue lifespan is elastic based on examples of low mortality rates continuing in very old age for some species. The longest living verified human was Jeanne Calment at 122 years old.
Recent demographic data analysis suggests the natural limit may be around 115 years, with a very low probability of anyone living beyond 125. However, other studies found mortality plateaus after 105, challenging the idea of a fixed limit.
Most experts still believe very long lifespans over 122 are statistically unlikely without major advances, and recent slowing of lifespan increases supports the view that maximum lifespan may have an upper bound.
As people live longer, diseases like Alzheimer’s and other neurodegenerative diseases account for an increasing share of deaths, as there are currently limited treatment options for them.
Dr. Thomas Perls studies centenarians (people over 100 years old) and found they can be classified into three groups: survivors who developed diseases after age 80, delayers who developed diseases after 80, and escapers who reached 100 without major diseases.
Dr. Perls’ research suggests centenarians stay healthy longer rather than living a long time with diseases. Genetics also plays a role in survival past extreme ages.
Dr. Perls runs a website that estimates lifespans based on factors like diet, exercise, stress levels, and family history. Maintaining independence late in life also correlates with longevity.
Steven Austad and S. Jay Olshansky made a bet that someone would live to 150, placing $150 each into a fund that could grow to $1 billion over 150 years to incentivize longevity research. They disagree on how rapidly medical advances could extend lifespans.
Aging occurs through the accumulation of molecular and cellular damage over time. Scientists study “hallmarks of aging” that are present and accelerate aging when increased or prolong life when reduced. Understanding these hallmarks may help defeat aging.
Genes contain the instructions for making proteins, which are essential molecules for life that regulate cell processes, enable cell communication, sensory functions, the nervous system, immunity, and more.
Genetic information is stored in DNA molecules in the form of a double helix, with two strands made of alternating sugar and phosphate groups linked together via pairs of nitrogenous bases (A, T, C, G). This structure allows DNA to duplicate itself.
During gene expression, a portion of DNA is copied into messenger RNA (mRNA), which leaves the nucleus and directs protein production by ribosomes in the cytoplasm.
The mRNA nucleotide sequence is read three bases at a time (codons), and each codon specifies an amino acid that gets linked together to form a protein chain with a unique 3D shape and function.
Aside from protein-coding sequences, genes also contain non-coding regulatory sequences that control when and how much of a protein is made. Gene expression is finely tuned through a complex network of interactions between genes and the cellular environment.
Over time, the DNA molecule itself can accumulate mutations through changes in its nucleotide bases. Most mutations have no effect, but some can impair proteins or alter their expression patterns, contributing to aging and disease. Understanding genetics at the molecular level has transformed biology.
Mutations can increase genetic variability in a population and make it more resilient to changes in environment or climate. Without mutations, there would be no evolution.
Loss of control in biology, like cancer, occurs when cells multiply unchecked and interfere with organ functioning. Cancer and aging arise from biological loss of control related to mutations in genes due to DNA changes.
Early evidence linked environmental factors to mutations and cancer. Experiments in the 18th-19th centuries found chimney sweeps had high cancer rates from soot exposure. Applying coal tar to rabbits caused skin cancer.
Hermann Muller’s experiments in the 1920s showed X-rays caused a dramatic increase in lethal mutations in fruit flies, providing direct evidence linking radiation to mutations.
Charlotte Auerbach and colleagues later found mustard gas exposure also increased lethal mutations in fruit flies, showing chemicals can cause genetic mutations too.
Understanding how environmental agents damage DNA to cause mutations became a key question after Watson and Crick’s DNA discovery. Oak Ridge National Lab played a major role in radiation biology research after WWII.
Dick and Jane Hollaender were pioneering scientists in the field of DNA damage and repair. They worked together at Oak Ridge National Laboratory and Brookhaven National Laboratory over several decades, making important discoveries while also raising a family.
They studied how UV radiation causes thymine dimers, which link two adjacent thymine bases on DNA. This damages the DNA and prevents it from being copied.
Dick showed that thymine dimers prevented DNA from being copied, arresting bacterial growth. However, dimers were later removed from the DNA through a process called excision repair.
Separate research groups also discovered excision repair mechanisms around the same time. Later, it was found that some organisms like humans have a different DNA repair system instead of excision repair.
Tomas Lindahl showed that DNA is constantly under assault from spontaneous damage even without external threats like radiation. Water alone can cause around 10,000 changes per day to the DNA in each cell.
Lindahl and others later worked out mechanisms for repairing single base changes as well as double-strand breaks, which are critical to prevent genetic corruption and risks like cancer.
Accurate repair often uses the intact DNA in the other chromosome copy as a template to guide repair of breaks. This helps maintain genetic integrity.

DNA repair mechanisms are crucial for maintaining genetic integrity as cells divide and the genome is duplicated. Errors naturally occur during DNA replication, but repair enzymes work to correct mistakes and restore the correct DNA sequence.

Two key aspects of DNA repair were highlighted. First, during homologous recombination, the four DNA strands become intertwined to accurately join matching segments and fill in any gaps. This is more precise than randomly joining ends.

Second, DNA polymerases that replicate DNA are very accurate but still make errors. Cells have repair enzymes like mismatch repair to recognize and correct errors by excising the incorrect segment and filling in the right sequence. This maintains genomic stability during cell division.

Defects in DNA repair increase cancer and aging risks as damage accumulates over time. Many repair genes are conserved across species, highlighting their essential importance. The DNA damage response also triggers cellular outcomes like senescence or apoptosis that influence aging. DNA repair is crucial for maintaining health and longevity.

Alexis Carrel was a famous French surgeon who conducted early experiments trying to keep tissues alive indefinitely in culture at the Rockefeller Institute. In the early 1900s, he claimed to have found that cells from a chicken embryo could be maintained alive in culture for years, making them essentially immortal. This was widely reported and led to speculation that immortality may be achievable.

However, in the 1960s, Leonard Hayflick discovered that normal human cells actually have a finite lifespan and will stop dividing after a set number of times, which he termed the Hayflick limit. He showed that Carrel was mistaken, and cells are not immortal. Later experiments revealed that the ends of chromosomes, called telomeres, get progressively shorter each time a cell divides, explaining the Hayflick limit.

It’s possible Carrel unknowingly reintroduced fresh cells to his long-term culture. His fame and power may have also made him arrogant and less critical of his own research. Ultimately, his claim of immortal cells was incorrect and profoundly impacted our understanding of aging and cellular lifespan limits.

Here is a summary of key events in Elizabeth Blackburn’s life based on the passage:

She met her future husband John Sedat while studying in Cambridge. He soon accepted a position at Yale University.
As a result, Blackburn decided to join Joseph Gall’s lab at Yale for her postdoctoral research. Gall was interested in chromosome structure.
At Yale, Blackburn and Gall applied their combined expertise in DNA sequencing and cell biology to identify the sequence of DNA at telomeres, the ends of chromosomes.
They discovered repetitive sequences (TTGGGG in Tetrahymena) at telomeres that were different from the rest of the chromosome.
Blackburn then collaborated with Jack Szostak and showed that adding the Tetrahymena telomere sequence stabilized artificial chromosomes in yeast.
Later, as head of her own lab at UCSF, Blackburn discovered the enzyme telomerase with graduate student Carol Greider. Telomerase adds telomere repeat sequences.
This discovery explained how cells can divide indefinitely through telomere rebuilding, as cancer and germ-line cells do with their telomerase expression.

Here is a summary of the key points about our DNA:

DNA contains the genetic instructions that make us who we are. It sequences the approximately 3 billion base pairs that make up the human genome.
Only about 2% of our DNA directly codes for proteins. The rest was previously thought to be “junk DNA” but is now believed to have important functions that are not fully understood.
While DNA provides the blueprint, it does not alone determine our fate. Identical twins can differ, and epigenetic factors like environmental influences play a role in how genes are expressed.
The human genome project mapped the full sequence of human DNA but left gaps and did not reveal all gene functions. Further study is needed to understand DNA’s role fully.
DNA undergoes epigenetic changes that determine cell identity. Cells differentiate based on which genes are turned on or off in response to their environment, in a process described as “Waddington’s landscape.”
While DNA provides a genetic program, biological development is complex and non-deterministic, influenced by both genetic and non-genetic factors over a lifetime. The genome alone does not predestine our traits or health outcomes.
The fertilized egg (zygote) is called totipotent, meaning it can develop into any cell type needed to form a new organism, including the placenta.
After cell division, it becomes a blastocyst with an inner cell mass that forms the embryo and outer cells that form the placenta. The inner cells are pluripotent, meaning they can form any cell type of the body but not extraembryonic tissues.
Briggs and King found nuclei from early frog embryos could direct full development when transferred to enucleated eggs, but later-stage nuclei could only direct partial development.
Gurdon successfully transferred nuclei from differentiated intestinal cells of tadpoles into enucleated frog eggs, producing normal tadpoles, showing that differentiated cells retain full developmental potential in their genome.
This challenged the idea that differentiation was due to gene loss and showed it is due to gene expression changes. It was the first mammalian cloning, done later with Dolly the sheep in 1996.
Scientists wondered if embryonic-like stem cells could be induced to form any needed tissues like heart, neurons or pancreas for regenerative medicine or aging. Some tissues like skin can regenerate naturally through stem cells.
Stem cells can differentiate, or develop, into only a few different cell types. For example, hematopoietic stem cells can generate blood cells but not liver or heart cells. Embryonic stem (ES) cells are pluripotent and can develop into any cell type.
Scientists could culture and direct ES cells to develop into specific tissue types, fueling stem cell research. However, ES cells were derived from embryos, raising ethical issues.
Induced pluripotent stem (iPS) cells were later developed by reprogramming adult cells using transcription factors. This avoided the need for embryos and expanded stem cell research possibilities.
Stem cells are different from other cells because they contain many active transcription factors that allow them to proliferate indefinitely and develop into different cell types.
Epigenetic tags like DNA methylation help determine which genes are active or silenced in different cell types. These tags are passed down during cell division, helping maintain cell identity over generations. They also allow environmental exposures to have lasting impacts.
DNA is wrapped around histone proteins to form chromatin, adding another layer of gene regulation complexity in cells.
Histones are positively charged proteins that allow DNA to condense by wrapping and compacting the DNA into structures called nucleosomes. This compaction is essential for DNA to fit inside the tiny nucleus of the cell.
The first level of compaction is the nucleosome, where DNA wraps around histone proteins. Nucleosomes then organize into filaments that further compact the DNA.
Compaction allows DNA to fit in the nucleus, but the cell still needs to access genes when needed. Epigenetic modifications to histones, like acetylation, mark genes for transcription and make the DNA accessible even when highly compacted.
Histone modifications, along with DNA methylation, establish the epigenome - an additional layer of genetic control that helps cells retain their identity and regulates gene expression over time. The epigenome contributes to differences in aging rates between individuals and environments.
Biological clocks based on DNA methylation patterns can more accurately predict aging and age-related disease risk compared to chronological age alone. However, methylation clocks only reflect biological aging and are not diagnostic tools on their own.
The aging clock resets at conception through epigenetic reprogramming in germ cells and embryos, allowing each new individual to start with a “young” epigenome despite the parents’ age. This resets accumulated epigenetic changes from prior generations.
Neurodegenerative diseases like Alzheimer’s and Parkinson’s are becoming major causes of death as populations age. Alzheimer’s in particular is expected to affect over 100 million people worldwide by 2050.
These diseases involve the malfunction and accumulation of proteins in the brain. Proteins normally fold into precise 3D shapes to function properly, but sometimes fold incorrectly.
In Alzheimer’s, two proteins called amyloid plaques and tau tangles accumulate abnormally in the brain, damaging neurons. This leads to cognitive decline and memory loss. As the disease progresses, patients lose basic abilities like eating and recognition of family.
While the biology of these diseases is now better understood, there are still no effective treatments to stop or reverse the progression. Dementia poses a major health challenge as populations continue to age. Stem cell therapy and other regenerative approaches are areas of active research aimed at restoring damaged tissues.
Cells, like households, need to get rid of faulty, damaged, or unneeded products/proteins to function properly.
Proteins can be defective from manufacturing (ribosome errors) or misfolding. They can also become damaged or unneeded over time.
Cells have evolved quality control systems like chaperone proteins to refold misfolded proteins.
The unfolded protein response detects protein folding issues and ramps up chaperones or targets proteins for destruction.
Ubiquitin tags defective/unwanted proteins so they can be degraded by the proteasome, which chops proteins into recyclable pieces.
The proteasome and ubiquitin systems decline with age, leading to protein accumulation and diseases. Defects in these systems are also linked to aging and age-related diseases.
For larger protein complexes, cells use lysosomes which can engulf and break down larger unwanted “junk,” analogous to how we dispose of large unwanted items.
Cells have finely-tuned protein quality control and degradation systems, but defects accumulate with age, contributing to age-related disease pathology.

The passage discusses cellular structures called lysosomes and their role in recycling the cell’s waste through a process called autophagy. In the 1950s, scientist Christian de Duve discovered lysosomes, which contain digestive enzymes. They break down unwanted cellular structures that are engulfed by autophagosomes and delivered to lysosomes.

In the late 1980s and early 1990s, scientist Yoshinori Ohsumi studied autophagy in yeast and was able to identify genes essential for the process. His work revealed that autophagy happens continually as part of normal cell maintenance and can be upregulated during stresses like starvation. It also plays an important role in development by breaking down cellular structures as cells differentiate.

The passage goes on to discuss how cells regulate protein production during stresses through a process called the integrated stress response (ISR). ISR shuts down most protein synthesis while allowing production of stress-response proteins. While initially thought to always be beneficial, some evidence suggests overactive ISR could be pathological in certain conditions like Alzheimer’s. Studies inhibiting ISR have shown potential benefits, suggesting the optimal level may depend on circumstances. Understanding ISR modulation is a focus of aging research.

In summary, the key points are about lysosomal and autophagic recycling of cellular waste, as well as stress response pathways that regulate protein production under stress conditions in order to maintain proper protein homeostasis and cellular function.

Here are the key points about how cells sense problems and attempt to correct them:

Cells have a complex network of proteins that monitor their internal conditions and detect when things are not right. This includes sensing metabolic imbalances, damage, toxins, invading pathogens, etc.
Control proteins regulate the response by turning on or off other proteins that carry out corrective functions. Examples include altering gene expression, triggering repair mechanisms, activating the immune response, inducing cell death, etc.
As we age, these control proteins can become defective, throwing off the entire regulatory system. Problems are amplified as the cell loses its ability to properly detect and respond to issues.
This breakdown in cellular homeostasis and response contributes to age-related diseases like Alzheimer’s. Things the cell can no longer correct, like abnormal protein clumping, accumulate over time and lead to neurodegeneration.

So in summary, cells have elaborate feedback loops to maintain normal function, but aging can compromise these control systems, making cells less able to fix problems and more prone to disease. Diseases result from an accumulation of cellular issues that can no longer be properly addressed.

Studies in rodents and other species have found that calorie restriction (CR), where animals are fed 30-50% fewer calories than they would consume voluntarily while maintaining good nutrition, leads to significant increases in both average and maximum lifespan. The animals on CR also show delays in aging-related diseases like diabetes, heart disease, cognitive decline, and cancer.
Early studies in monkeys also found benefits of CR, but more recent long-term studies have had less conclusive or even contradictory results. A 2009 study found CR extended lifespan in rhesus monkeys, but a 25-year NIA study found no difference between CR and control groups already on a healthy, non-obesity promoting diet.
The contradictory monkey studies suggest that for animals already on a healthy diet and not overweight, further calorie restriction provides little additional benefit to longevity. Maintaining a moderate, healthy diet may be more important than severe calorie restriction. However, calorie restriction still seems to provide benefits in rodent studies and for overweight populations.
The study showed that calorie-restricted (CR) animals weighed more than wild animals, suggesting even the restricted diet provided more food than they would eat naturally.
Long-term CR studies in monkeys are difficult due to their long lifespans (25-40 years) and high costs of multi-decade studies. Similar long-term human CR studies are not feasible.
Intermittent fasting techniques like the 5:2 diet or eating within a daily window are claimed to be beneficial, but evidence is anecdotal.
A study found aligning feeding times to circadian rhythms improved intermittent fasting benefits in mice. However, the additional benefit may have been due to disrupting sleep to obtain food when normally asleep, rather than timing of feeding itself.
Lack of sleep increases disease risk and accelerates aging. One way it does this is by altering cellular damage repair mechanisms. However, the CR study did not explicitly monitor sleep patterns.
While many lab studies find CR benefits numerous species, one study found varied effects by mouse strain and sex, and some experts question if CR truly extends lifespan or just prevents overfeeding issues. Evidence is also mixed in wild animals.
Overall, most aging scientists agree CR extends healthy lifespan in mice and reduces mortality/disease risk in humans versus an unlimited diet. But CR is difficult for humans due to perpetual hunger and lack of evolutionary adaptation to restriction.
The summary describes a breakthrough in understanding the target of the immunosuppressive drug rapamycin. It involved an unexpected collaboration between American scientist Michael Hall, working in Basel, Switzerland, American Joe Heitman, and Indian scientist Rao Movva from Sandoz pharmaceutical company.
Heitman joined Hall’s lab in Basel and proposed studying immunosuppressants using yeast mutants resistant to cyclosporine. Hall connected Heitman with Movva at Sandoz, who provided a rare sample of rapamycin.
Experimenting with yeast mutants, they identified two related genes, TOR1 and TOR2, that coded for large proteins targeted by rapamycin. This was a major breakthrough in understanding how rapamycin works.
Further work by Hall, Heitman, and others showed that TOR proteins actively stimulate cell growth by sensing nutrients. This challenged the prevailing view that cells passively grow with nutrients.
While Hall’s group made the original discovery, some US groups claiming the same target in mammals led to confusion over nomenclature before it was standardized as mTOR. The collaboration between the three scientists from different backgrounds led to an important unexpected insight.
Michael Hall’s conclusions about TOR represented a paradigm shift in cell growth understanding, contradicting decades of prior work. His paper was rejected seven times before publication in 1996.
TOR is a kinase that acts as a major hub, connecting to many other proteins. It has widespread effects in the cell by phosphorylating other proteins to turn pathways on and off.
TOR exists in two complexes, TORC1 and TORC2. TORC1 senses nutrients and energy levels and promotes protein synthesis, nucleotide and lipid production.
TOR inhibits autophagy under good conditions but activates it under caloric restriction or stress when nutrients are limited. This links TOR to autophagy and energy control.
Rapamycin inhibition of TOR mimics some effects of caloric restriction like autophagy induction and longevity in many organisms. However, long-term rapamycin use risks immune suppression and infection.
Studies are ongoing to better understand rapamycin’s effects and safety profile, including a study using domestic dogs to examine rapamycin’s impact on aging in a more natural environment. More research is still needed before considering rapamycin as an anti-aging treatment in humans.
Studies on twins had suggested only about 25% of human longevity is genetically determined. A lowly worm, C. elegans, helped overturn that view.
C. elegans was identified as an ideal model organism by Sydney Brenner due to its small size, short life cycle, transparency, and ability to be easily cultivated. Its cells could be mapped out during development.
Worms typically live 2 weeks but can go dormant for up to 2 months in the “dauer” state, suspending aging. Only juveniles can do this.
David Hirsh and Michael Klass showed worms age little in dauer and isolated long-lived mutants, suggesting genetic factors.
Tom Johnson found single mutations in the age-1 gene that more than doubled worms’ maximum lifespan, challenging the view that many genes each contribute slightly to longevity.
Cynthia Kenyon was inspired by Johnson’s work to investigate aging and discovered another long-lived mutant, further supporting the role of single genes in determining lifespan. C. elegans helped establish aging as genetically determined and amenable to study.
Kenyon focused on the DAF genes, previously identified genes in C. elegans that affect dauer formation and longevity.
She used temperature-sensitive mutants that could develop normally at lower temperatures to avoid dauer formation influencing lifespan. This allowed her to measure lifespan without dauer formation being a factor.
Kenyon identified a mutation in the DAF-2 gene that doubled C. elegans lifespan. This paper was well received unlike Johnson’s earlier work.
Ruvkun sequenced the DAF-2 gene and found it coded for an insulin-like growth factor receptor. This linked the growth hormone/insulin pathway to longevity control.
Further work found DAF-2 activates a kinase cascade culminating in the DAF-16 transcription factor. DAF-16 activates stress response and protein maintenance genes to extend lifespan.
This pathway helps explain how single gene mutations can have large lifespan effects through cumulative changes to many gene expressions.
There is interest in drugs other than rapamycin that act on pathways besides TOR, such as the IGF-1 pathway. Metformin is a drug currently being studied.
Metformin is already used as a treatment for type 2 diabetes. Its exact mechanism of action is complex and not fully understood, but it involves inhibiting a mitochondrial protein and affecting components of the IGF pathway.
Some early studies in mice and humans suggested metformin could extend lifespan, but subsequent studies have questioned these results and found metformin’s effects on longevity are unclear and not as strong as rapamycin.
A large ongoing clinical trial called TAME is studying whether metformin can delay aging-related diseases in healthy older adults, but the evidence for its benefits concerning longevity is currently inconclusive given some potential drawbacks noted in studies.
While metformin’s long-term safety profile is known from diabetics using it, more research is still needed before recommending its long-term use just for longevity benefits in healthy individuals without diabetes.
Decades of research provided scientific evidence that caloric restriction (CR), or reducing calorie intake without malnutrition, can prolong healthy life in various organisms compared to eating ad libitum.
In the last few decades, two major aging-related pathways in cells were discovered - TOR (target of rapamycin) and IGF-1 (insulin-like growth factor 1). CR was shown to affect these pathways.
Discovering these pathways opened up possibilities for extending lifespan by targeting them with drugs like rapamycin and metformin, though more work is needed to establish efficacy and safety.
The discoveries of TOR and IGF-1 were surprising in that scientists weren’t initially looking for aging connections. They revealed key cellular processes with implications for aging and disease.
Further research in yeast identified the Sir2 gene, a histone deacetylase. Increasing Sir2 extended yeast lifespan. Sir2 also had counterparts in other species like flies and worms.
This prompted speculation that targeting sirtuins like mammalian SIRT1 could mimic the benefits of CR. Resveratrol was identified as a potential SIRT1 activator, fueling interest in health effects of red wine.
However, later studies cast doubt on the links between Sir2/sirtuins and CR as well as resveratrol’s effects. More research is still needed to validate potential anti-aging therapies targeting these pathways.
Around 2 billion years ago, one ancient cell engulfed another simpler, smaller cell in what is known as endosymbiosis. Normally this results in one cell being digested or both cells dying, but in this case both cells survived and learned to cooperate.
This theory, known as the endosymbiotic theory, was proposed in the early 1900s by Russian botanist Konstantin Mereschkowski but gained more acceptance in the 1960s when American biologist Lynn Margulis championed it.
The engulfed cell became an organelle called the mitochondrion, which provides energy for the larger host cell. This allowed cells to become more complex with specialized parts, eventually evolving into multicellular organisms like humans and animals.
Mitochondria were once free-living bacteria but are now necessary components of our cells. Their DNA is separate from our nuclear DNA, providing evidence they were once separate entities that merged.
This singular event of endosymbiosis allowed for the evolution of advanced eukaryotic life like plants and animals from simpler prokaryotic cells like bacteria. It is a key reason why cells and organisms became more complex over time.
Lynn Margulis was an American scientist who proposed the endosymbiotic theory that eukaryotic cells developed from incorporated prokaryotic cells (like bacteria). She believed symbiosis was widespread in evolution.
At the time, the prevailing view was that simpler bacteria evolved slowly into more complex cells. Margulis proposed that mitochondria and chloroplasts descended from symbiotic bacteria that came to live inside cells.
She suggested these organelles perform important functions like energy production (mitochondria) and photosynthesis (chloroplasts) that provided advantages for the host cell.
Today her endosymbiotic theory is widely accepted. Mitochondria are thought to have originated from archaea swallowing bacteria around 2 billion years ago.
Margulis had some controversial views as well, questioning the scientific consensus around issues like the causality of HIV/AIDS and involvement in 9/11 conspiracy theories.
Her proposal of the endosymbiotic origin of eukaryotes was a major contribution despite facing initial rejection, and revolutionized understanding of cellular evolution and life’s diversity.
Mitochondria are specialized organelles that have different lipid compositions in different cell types to perform specialized functions. They exchange components with other organelles to help each other make needed lipids. Excess contact can be harmful.
Beyond making ATP, mitochondria are involved in later stages of sugar metabolism and burning stored fat. They produce signals regulating cellular energy levels and gene/pathway activity. They are now central to metabolism, not just energy factories.
Mitochondria accumulate defects with age and produce energy less efficiently. Their shape changes from elongated to spherical. Aging mitochondria contribute to declining health and energy levels.
If mitochondria can’t produce enough ATP, cells like neurons die, causing brain death. Gradual mitochondrial decline leads to this point over normal aging.
Free radicals produced during mitochondrial metabolism as a byproduct of oxygen use damage cells over time, accelerating aging. Damage accumulates and is passed to new mitochondria through mutations. This contributes to mitochondrial and cellular decline.
While antioxidant supplements were thought to help, studies show they do not reduce mortality and may increase it. Free radicals also have cell signaling roles. Their effects on aging are more complex than initially thought.
Mitochondrial DNA mutation rate correlates with aging and disease. Mice engineered to mutate DNA faster showed premature aging, indicating mutations may drive aging processes.
The author attempted the 200-mile Coast-to-Coast walk across England but had to abandon it a few days short due to knee problems. An inspection found a torn and inflamed meniscus from osteoarthritis.
Soon after knee repair surgery, the author’s shoulder started aching, also from osteoarthritis. Joint pain from aging is common amongst friends.
Joint pain represents one type of inflammation from physical wear and tear on joints. But as we age, there is a more pervasive low-level chronic inflammation called “inflammaging” that also affects health.
Inflammaging is partly due to aging mitochondria in cells rupturing and leaking contents that trigger an inflammatory response, as the cell mistakes it for a bacterial infection.
Neurons are particularly affected by aging mitochondria, which may contribute to declining cognitive abilities. Maintaining healthy mitochondria is key to longevity. Exercise and caloric restriction can help produce new mitochondria.
Over time, accumulating defects in individual cells lead to tissue and organ dysfunction associated with aging symptoms like arthritis and infections. The interconnected nature of aging processes was discussed.
Cells can respond to DNA damage in three ways: repair it if mild, trigger cell death if extensive, or enter a senescent state if unable to divide. Senescence prevents damaged cells from reproducing and potentially becoming cancerous.
However, senescent cellsaccumulate with age due to constant DNA damage and inflammation over time. They disrupt tissue function and promote further aging.
Studies in mice show removing senescent cells can delay aging effects and extend lifespan, confirming their role in driving aging.
Tissues are constantly regenerated by stem cells. But with age, stem cells decline in number and balance of self-renewal vs differentiation. They also accumulate damage and mutations, impairing regeneration.
This results in loss of tissue function and frailty. Can scientists reprogram remaining stem cells to reverse aging effects by regenerating youthful stem cell populations? This approach aims to restore the decline in tissue regeneration driving human aging.
Reprogramming cells fully with Yamanaka factors to create iPS cells often leads to tumors like teratomas when used to grow new tissues. This is because the factors don’t precisely reverse development and iPS cells are not identical to embryonic stem cells.
Exposing cells only transiently to the factors may partially reverse development and rejuvenate tissues without risks of pluripotency. Studies found this approach improved health biomarkers and extended lifespan in mice.
Introducing three Yamanaka factors to injured adult mice enabled optic nerve regeneration and vision recovery. The factors reversed aging-related epigenetic changes and DNA damage in other experiments.
Parabiosis studies connecting the circulatory systems of young and old animals found young blood improved various health metrics in older partners. However, risks of immune rejection and dependence on the younger partner’s functioning organs remain issues. More studies are needed before applications to humans.
Early human trials transfusing young plasma faced criticism for lack of safety data and prompted FDA warnings against unregulated use for aging. Further controlled studies are required to validate any anti-aging effects.

Here is a brief summary:

Cryonics seeks to preserve humans who have died by rapidly freezing their bodies, with the hope that future medical advances could potentially revive them. Robert Ettinger was a pioneer who founded the Cryonics Institute.
Critics argue it is premature without proper clinical trials, while supporters believe waiting for full validation is denying patients access to a treatment they want.
Some wealthy individuals have undergone experimental “young blood transfusions” from younger donors, hoping it will have anti-aging effects. However, most scientists remain skeptical without further research.
Significant progress has been made in identifying aging-related factors in blood and their effects, but developing verified anti-aging treatments remains a long-term research goal, not something currently available to the public.
Cryonics facilities like Alcor freeze bodies or brains at very cold temperatures, typically in liquid nitrogen, with the hope that future technologies may be able to revive people. Bodies are drained of blood and replaced with antifreeze before freezing.
Transhumanists want to preserve human consciousness and minds indefinitely, either by freezing brains or eventually uploading minds to computers. They see intelligence as unique and important.
Cryonics faces major scientific hurdles. Bodies undergo biochemical changes after death that freezing may not undo. Mapping brain connections (connectomics) is still limited and static - it wouldn’t capture a brain’s constantly changing state. Brains also rely on physiological interactions with the body.
There is no evidence freezing can truly preserve human brains or memories intact for revival. Even if connections were mapped, it may not be enough to reconstruct or simulate a functioning brain.
Some influential figures like Elon Musk, Peter Thiel and Ray Kurzweil have expressed interest in cryonics, hoping future technologies could solve the challenges. However, most scientists remain skeptical it will ever work as intended.
Legal and ethical issues around consent and marketing cryonics, especially to vulnerable people, have also been debated based on cases like a British teen seeking cryopreservation.
Aubrey de Grey is a computer scientist turned biogerontologist who believes that aging is solvable and the first humans who will live to 1,000 have already been born.
He proposed a plan called SENS to achieve “longevity escape velocity” by addressing 7 issues that cause aging, like cell loss and stem cell deterioration.
Mainstream gerontologists criticized SENS as not scientifically validated. de Grey compared criticism to past objections to inventions like airplanes.
de Grey moved his SENS Foundation to the US after lack of UK support. He later divorced and made comments about relationships changing as aging is solved.
de Grey was accused of sexual harassment and fired from SENS Foundation but started a new group called LEV Foundation.
David Sinclair is another prominent researcher who predicts vastly extended lifespans but draws criticism for excessive claims not backed by evidence from things like resveratrol supplements he promotes.
In the past there was hype around anti-aging products but gerontologists said in 2002 that eliminating all aging causes might extend life 15 years at most. They opposed untested supplements and said eternal life was still unlikely.
There has been an explosion in the anti-aging industry over the past two decades, with over 700 biotech companies focused on aging and longevity research with a combined market cap of over $30 billion. However, many have yet to produce any actual products or therapies.
Companies sell nutraceutical supplements that don’t require FDA approval or clinical testing, despite claims about their anti-aging effects. However, having distinguished scientists on advisory boards gives the impression of credibility.
Tech billionaires have poured billions into companies like Altos Labs due to their belief that aging can be solved like an engineering problem through massive funding. However, aging is far more complex than software problems.
Promising research areas include targeting protein accumulation, mimicking calorie restriction through drugs like rapamycin and metformin, targeting senescent cells, identifying youth factors in blood, and reprogramming cells to reverse aging effects. Cell reprogramming is a major focus but safety and efficacy for aging remains uncertain.
Overall progress has been slow despite huge investments, and more rigorous testing will still be needed to translate any lab findings into proven anti-aging therapies for humans. The field has become more scientifically rigorous over time but still has a long way to go.
Anti-aging researchers face significant challenges in assessing whether their treatments are working, as the customary clinical trials are impractical due to the long timeframes needed to observe changes in aging.
Twenty years ago, there were no reliable biomarkers of aging that could be used to more quickly measure treatment effects. But now there are various biomarkers like epigenetic clocks, inflammation markers, hormone levels, etc. that may allow earlier assessment.
Regulatory hurdles also exist as clinical trials are usually only approved for disease treatment, yet aging is not clearly defined as a disease by regulatory bodies. This debate centers around whether aging is an inevitable normal process versus a disease.
The goal of “compressing morbidity” by reducing time spent in poor health is debated, as treatments targeting aging diseases may simply extend life and disability time. Available data suggests disability-free life has increased but disability time as a fraction of life has not decreased.
True compression of morbidity as envisioned may not be possible or humane given that aging naturally involves declining health and increased vulnerability over long lifespans. Overall healthspan extension remains a challenge for anti-aging research.
True compression of morbidity, where death occurs suddenly in otherwise healthy individuals, does not represent progress towards increasing healthspans.
Studying supercentenarians (those who live past 105 years old) provides hope that achieving health up until a fixed maximum lifespan is possible through genetic and lifestyle factors. However, even supercentenarians experience age-related decline in late life.
Advances in aging research could have significant societal consequences if healthspans are extended, such as straining retirement and healthcare systems, increasing inequality between rich and poor, and exacerbating overpopulation issues. These long-term impacts need careful consideration to avoid unintended outcomes. While individual longevity may be valued, changes at the societal level could be profoundly disruptive without adequate preparation and policy changes. Overall, the essay urges a measured approach to life extension research that considers both benefits and challenges.
Past increases in longevity have led to population growth because fertility rates remained high even as life expectancy increased. However, all societies eventually experience a demographic transition where birth rates fall as standards of living rise.
In developed countries that have already transitioned, further longevity gains may not necessarily lead to more population growth. Places like Japan have seen longevity increase while population declines due to low birth rates.
Fertility rates are below replacement levels in many countries and the average age of childbearing is rising. These trends result from greater security, prosperity, and women’s emancipation. They have slowed population growth, benefiting the environment.
If longevity surges past 100 years, population growth can be prevented by even lower birth rates or later childbearing. But delaying childbearing pushes against biological limits, and having very few children burdens a shrinking younger population supporting more elderly people.
To support aging populations, careers may need to extend into the 70s, 80s or beyond. But physically demanding jobs may be difficult for older workers, and pushing retirement ages higher is controversial.
In general, individuals tend to do their most innovative and creative work when younger, not only in science and business but also literature and arts. Maintaining high-quality work at very advanced ages is rare.
The passage discusses the impact of age on creativity and cognitive abilities. While some creative fields like filmmaking may remain strong in old age, most research suggests creativity declines with age, particularly for novel breakthroughs.
Cognitive abilities generally decline starting around age 45, with faster declines after 60. Areas like vocabulary remain stable longer than fluid abilities. Learning new skills gets harder with age.
The accumulation of knowledge and wisdom may peak around age 30. After that, people become more set in their views and prone to biases and reactionary thinking.
There is an imbalance of power favoring the old, who have more wealth and political influence. This can suppress new ideas from youth. Academia in particular has issues with tenure and lack of mandatory retirement ages.
While experience is valuable, intergenerational fairness is a concern if the elderly block opportunities for younger people. Flexible retirement assessments rather than rigid ages are suggested to balance these issues.
The evidence on differences in productivity between younger and older workers is mixed, with some studies finding older workers better due to experience and others finding no difference. A flexible, individualized approach to work and retirement is needed.
Keeping older adults engaged, active and socially integrated is important for well-being. They can still contribute positively through mentorship, civic activities and sharing their expertise even after formal retirement.
If lifespans increase dramatically, issues around retirement, resource use, and social/generational change would be magnified. However, advocates for long life extension have few concrete solutions beyond addressing problems as they arise.
While many pursue life extension, longer lives may not necessarily increase satisfaction and meaning. Mortality gives humans urgency and purpose that could be lost with indefinite lifespans. Societal stagnation is also a risk if generations don’t turnover.
Most humans intensely fear death yet wish to live as long as possible even with declining health. Views on long life extension are mixed, with benefits acknowledged but concerns about societal and resource impacts as well as unequal access. Individual attitudes differ from abstract support.

The passage discusses the relationship between cancer, aging research, and the potential for anti-aging advances. Some key points:

Cancer and aging are both highly complex biological processes with many interconnected causes. Cancer research has advanced treatment but not yet found cures, and aging research may follow a similar trajectory of steady improvements over time.
Today’s level of talent and funding in aging research mirrors the “war on cancer” efforts of past decades. Breakthroughs in lifespan extension may take time to materialize but will likely happen eventually, just as cancer treatments improved steadily.
The anti-aging industry is generating hype but also real research that could lead to disappointment in the short-term but major advances long-term, following Amara’s law about underestimating new technologies’ long-term effects.
While waiting for scientific breakthroughs, tried-and-true lifestyle habits like diet, exercise and sleep that are backed by biology can help people live well as aging research progresses.
Both the opportunities and ethical challenges of anti-aging technologies deserve consideration from researchers, governments and citizens to avoid unintended consequences down the line.

Here is a summary of the key points from the sources provided:

Life in Organisms, Cities, Economies, and Companies does not provide an overview, as it was not summarized. It appears to be a book about similarities in how life, social systems, and companies organize and function.
Hydras are small aquatic animals capable of regenerating lost body parts. They can regrow entire bodies from fragmented pieces. Regeneration is a complex process involving coordinated gene expression and chromatin regulation.
Turritopsis dohrnii is an immortal jellyfish capable of reverting from its sexually mature form back into its juvenile polyp form, achieving biological immortality. Comparative genomics of mortal and immortal cnidarians has provided insights into genes and proteins involved in rejuvenation.
Larger animals generally live longer than smaller animals of similar taxonomy. They have lower mass-specific metabolic rates and generation times. Studies have found diverse aging rates in different types of ectothermic tetrapods and turtles challenging theories of universal senescence.
Bats and marsupials provide evidence that longer-lived species invest more in somatic maintenance and repair, with a lower ratio of metabolic rate to body mass (lower “LQ” ratio). Species like naked mole-rats show trade-offs between longevity and reproduction.
Humans live decades past peak reproduction, unlike most mammals. Theories seek to explain the evolution of this unusual longevity, such as the grandmother hypothesis of post-reproductive individuals providing benefits.
In summary, regeneration abilities, genetic reprogramming, metabolic trade-offs, and evolutionary hypotheses were discussed in relation to organismal longevity, senescence, and aging across different species.
The articles discuss aging and longevity across different vertebrate species. While some animals like tortoises can live over 100 years, bats generally do not live as long, with 20 years being rare.
Factors like body size, metabolism, and ability to hibernate influence longevity. Smaller bats live shorter due to their higher metabolic rates. Hibernation allows longer-lived species to conserve energy.
Rochelle Buffenstein’s work on naked mole-rats showed they are cancer resistant and do not show increasing mortality risks with age. Their cells are resistant to genetic damage and do not proliferate abnormally.
Disagreements exist around theories of aging processes and limits to human longevity. While Olshansky predicted an upper limit of 115 years, others argue aging mechanisms differ across species and longevity is not inevitable. Evidence suggests no fixed limit to life expectancy gains.
Continued research seeks to better understand biological processes underlying aging and potential interventions. Areas of focus include DNA damage response mechanisms, cellular senescence, proteostasis, metabolism, and genetic/epigenetic factors influencing longevity.
In the early 20th century, scientist Alexis Carrel claimed that cells could be kept alive indefinitely in culture, contradicting the idea that cells have a limited lifespan. However, his claims could not be replicated.
In the 1960s, Leonard Hayflick discovered that normal human cells undergo a limited number of divisions before entering senescence, termed the Hayflick limit. This supported the idea that cells do have a finite lifespan.
The ends of chromosomes, called telomeres, gradually shorten with each cell division due to the end-replication problem. This occurs because DNA polymerase cannot fully replicate the 3’ ends of linear DNA strands.
In the late 1970s, studies in the ciliate Tetrahymena revealed that telomeres contain repetitive TTAGGG sequences. Researchers later discovered the enzyme telomerase that adds back TTAGGG repeats to telomeres.
Without telomerase activity to replenish telomere repeats, telomeres will shorten with each cell division until a critical length is reached, triggering senescence via the Hayflick limit.
A protein complex called shelterin associates with telomeres and protects their ends from being recognized as double-strand breaks. This allows telomeres to avoid DNA damage responses that would otherwise cause cell cycle arrest or apoptosis.

So in summary, the discovery of telomeres, telomerase, and shelterin helped explain the molecular basis of the finite cellular replicative lifespan originally described by Hayflick. Telomere shortening acts as a biological clock that limits the number of divisions a normal cell can undergo.

Here is a summary of the key points about biological aging and epigenetics from the passages:

Telomeres act as a biological clock and shorten with each cell division, eventually leading to cellular senescence. Their shortening is affected by lifestyle factors like stress. Telomerase can counteract shortening.
Epigenetic modifications like DNA methylation also change with age in predictable ways. Stress in early life, like famine, can leave epigenetic marks that increase disease risk decades later.
Steve Horvath developed an “epigenetic clock” based on DNA methylation levels at certain sites that closely correlates with biological age. It predicts longevity and healthspan in diverse organisms.
Methylation patterns accumulate gradually over time and reflect an organism’s exposure to various influences. They provide a flexible, molecular record of aging that influences gene expression and links environment to health. Resetting or slowing epigenetic clocks may help increase healthy lifespans.
While telomeres and epigenetics influence aging, there is still a delicate balance - too little or too much of certain factors like telomerase can be detrimental. More research is exploring how to optimize these mechanisms to delay aging.
Researchers developed epigenetic clocks that use DNA methylation patterns to measure biological age. Studies found the clocks reflect aging rates across tissues and species.
A study found honeybee queen and worker castes have distinct epigenetic patterns established during larval development, suggesting diet can influence epigenetics.
Germline cells undergo fewer cell divisions than somatic cells, resulting in fewer random mutations accumulating over time.
Even within embryos, cell competition acts as a quality control mechanism to eliminate cells with defects like mitochondrial problems, ensuring healthy development.
Fertilized eggs need nuclei from both parents to develop normally, reducing the impact of random epigenetic changes. Cloning studies found clones can live as long as naturally conceived animals.
Reprogramming somatic cells to an embryonic-like state through cloning or other techniques may potentially rejuvenate the epigenome and counteract aging effects. This represents a possible route to rejuvenating the whole organism.

Here is a summary of the key points from the papers:

“Lifespan, Improves Motor Performance and Attenuates Motor Neuron Loss in the SOD1 G93A Mouse Model of Amyotrophic Lateral Sclerosis”

Study finds that calorie restriction (CR) extends lifespan and improves motor performance in mice with ALS, a neurodegenerative disease. CR also attenuates motor neuron loss. This suggests CR may have benefits for ALS.

“Preventing Proteostasis Diseases by Selective Inhibition of a Phosphatase Regulatory Subunit”

Identifies a regulatory protein, PPP1R15A, involved in protein folding. Inhibiting it prevented proteotoxicity and extended lifespan in a worm model of Parkinson’s and Alzheimer’s disease. Suggests targeting this protein could be a treatment strategy for neurodegeneration.

“PPP1R15A-Mediated Dephosphorylation of eIF2α Is Unaffected by Sephin1 or Guanabenz”

Follow up study finding that drugs Sephin1 and Guanabenz, which were thought to work via PPP1R15A, did not actually affect its phosphorylation of eIF2α. Questions whether these drugs directly target the integrated stress response pathway.

Deleting genes for eIF2α kinases alleviates Alzheimer’s disease phenotypes in mice. Suggests reducing integrated stress response signaling could be beneficial for Alzheimer’s.
Molecule ISRIB reverses effects of phosphorylated eIF2α and improves cognitive deficits in mice. Early but promising evidence it could be a treatment for various brain disorders by inhibiting integrated stress response.
Key researcher is Nahum Sonenberg, who discovered eIF4E and the role of translation initiation in cancer. He remains an expert on protein synthesis and its relationship to disease.

The articles discuss two studies on the effects of calorie restriction (CR) in monkeys. The Nature 2012 study found that CR did not significantly increase lifespan in rhesus monkeys as it does in rodents. The accompanying News article discussed how this calls into question whether CR extends lifespan in primates.
Other evidence suggests CR can extend lifespan in rodents but its effects in primates are unclear. Genetic differences may impact responses to CR. Intermittent fasting is a popular alternative to CR but its benefits compared to other diets are still debated.
A 2022 study found that circadian alignment of early-onset CR promoted longevity in mice by reducing oxidative stress and DNA damage. Commentaries discussed how this aligns CR benefits with normal feeding rhythms.
Sleep deprivation can accelerate aging by promoting reactive oxygen species in the gut. Lack of sleep is linked to earlier mortality. Genetic factors also influence lifespan responses to CR.
CR works in lab animals but may not confer the same benefits in wild animals facing environmental stresses. More research is needed on optimal CR protocols and their interaction with genetics and environment.
Rapamycin, an immunosuppressant drug, extends lifespan in diverse species by inhibiting the nutrient-sensing pathway TOR. This supported TOR’s role in aging and sparked research on drugs that target aging processes.
Studies on the effects of rapamycin in mice, including when begun later in life, supported its anti-aging effects. However, its immunosuppressive effects require caution in aging research and clinical use.
C. elegans aging research helped identify the insulin/IGF-1 signaling pathway as a conserved regulator of longevity. Mutations that extend lifespan in worms and flies provided evidence this pathway influences aging across species.

Here is a summary of the key points from the sources provided:

In 1993, Cynthia Kenyon and colleagues discovered that mutating the age-1 gene in C. elegans doubled their lifespan. This established longevity genes could be identified.
Further work identified additional genes in the insulin/IGF-1 signaling pathway that influence lifespan, including daf-2, age-1/daf-23, and daf-16. Mutations that reduce insulin/IGF-1 signaling lead to increased lifespan.
Lenny Guarente’s lab discovered that increasing the activity of Sir2, a longevity gene in yeast, extended lifespan. Sir2 was found to be an NAD-dependent deacetylase.
Work then showed that Sir2 activity was required for calorie restriction to extend lifespan in yeast and flies. Small molecules that increased Sir2 activity also increased lifespan.
This provided evidence that genetic or pharmaceutical interventions could target fundamental aging processes and extend healthy lifespan, establishing the field of geroscience. Many ongoing studies aim to further translate these findings.

The key ideas are the initial discoveries of longevity genes in C. elegans and insights into the conserved role of insulin/IGF-1 signaling, along with the seminal work on Sir2 showing specific genes can be manipulated to influence aging in a variety of species. This work helped establish the concept that aging may be malleable through genetic or pharmacological means.

Lynn Margulis proposed the endosymbiotic theory which suggests that mitochondria and chloroplasts originated as bacteria that were endosymbiotically acquired by larger cells. This theory is now widely accepted.
Mitochondria play a crucial role in generating ATP through oxidative phosphorylation to power cellular processes. The human body constantly generates high levels of ATP to meet the brain’s energy demands.
Mitochondria are maternally inherited and can be manipulated, as seen in three-parent baby techniques to prevent mitochondrial diseases. However, this may have long term effects that are not yet understood.
Mitochondrial dysfunction is linked to aging and diseases like Parkinson’s. The free radical theory of aging proposed in 1954 by Denham Harman suggests that reactive oxygen species produced during ATP generation damage cellular components over time.
Oxidative stress increases with age as mitochondrial function declines, contributing to the accumulation of damage that drives aging. Calorie restriction may protect against this by reducing free radical production.
In summary, Lynn Margulis’s endosymbiotic theory illuminated the bacterial origins of mitochondria, which play a central yet complex role in cellular energetics, inheritance, diseases, and the aging process through their production of reactive oxygen species.

Here is a summary of the key points from the sections provided:

Studies in mice have shown that removing senescent cells through genetic interventions can increase lifespan and delay age-related disorders. Senescent cells accumulate with age and secrete factors that damage surrounding tissues.
An oral cocktail of senolytic drugs was able to selectively eliminate senescent cells in older mice, improving physical function and increasing lifespan. This supports the idea that removing senescent cells can reverse some aspects of aging.
However, it is not strictly accurate that the entire human body replaces itself every 7 years. While cells in some tissues like gut or skin turnover quickly, other cells like neurons have very slow replacement rates if at all. Liver cells were found to have a lifespan of over 15 years in humans.
Accumulation of senescent cells is driven by the accumulation of cellular damage over time from factors like oxidative stress, DNA damage, and shortening of telomeres. Tumor suppressor genes p16INK4a and p53 play key roles in triggering and maintaining cellular senescence.
Senescent cells are thought to contribute to aging and age-related diseases through their senescence-associated secretory phenotype, secreting a range of factors that can harm surrounding tissues and drive inflammation.
Cryonics, or cryopreservation of human beings as a way to potentially revive them in the future, has been proposed as an idea for a long time but remains highly speculative and unproven.
Elon Musk is a proponent of cryonics and has said he would like to “die on Mars, just not on impact” implying he hopes to be revived in the future.
Successfully reviving a cryopreserved human being would be extremely difficult and complex, as it would require deducing the entire state of the brain and body down to the molecular level and reversing damage from freezing.
Some argue the point of cryonics is unclear if the current science and technology have no viable path to real revival. Revival would require medical advances far beyond what exists today.
A 14-year-old British girl who died of cancer was allowed by a court to be cryogenically frozen according to her wishes, sparking an ethical debate.
A leading UK scientist argued for restrictions on marketing of cryonics given its highly speculative nature and ability to give false hope to vulnerable people.

So in summary, it outlines some high-profile advocates of cryonics but also acknowledges major scientific hurdles and uncertainties, as well as ethical debates around its marketing and use.

Here are summaries of the key passages:

The first passage discusses a 2016 article in The Guardian where a top UK scientist called for restrictions on the marketing of cryonics, arguing it gives false hope.
The second passage describes a 2003 Sports Illustrated article that provided new details about the controversial cryopreservation of baseball legend Ted Williams after his death, including claims he was decapitated.
Various press reports indicate futurist Nick Bostrom has arranged for his body to be cryopreserved after death, though he did not confirm this directly when contacted by the author.
In 2018, a startup called Nectome pitched a service involving chemical preservation of the brain that would be “100 percent fatal.” After backlash, the founder said the goal was to help research, not provide immortality.
Amatuer mathematician Michael Schirber solved a decades-old graph theory problem early in his career before turning to aging research.
Anti-aging researcher Aubrey de Grey argues the first humans to live to 1000 may already have been born and aging can be addressed by solving seven biological problems. Some mainstream scientists are skeptical of these claims.
De Grey was fired from the SENS Research Foundation in 2021 over allegations of interfering in an investigation into his conduct. He continues his work through a new organization.
Longevity researcher David Sinclair has made bold predictions about extending lifespan but others say he overstates what is possible; his book was also strongly criticized in a review.
California tech billionaires are major funders of anti-aging companies like Altos Labs in hopes of extending healthy lifespans based on their experiences wanting to overcome limits as young entrepreneurs. However, mainstream aging researchers remain cautious about such claims.

#book-summary

Why We Die - Venki Ramakrishnan