Juvenescence

Juvenescence by Jim Mellon and Al Chalabi is a book aimed squarely at investors who want to invest in the new hot thing and get better than average returns. I personally am not on board with the long-term ability of people/groups/investors to do this (A Random Walk Down Wall Street), but at the same time I’m very interested in the field and this book provides a good helicopter view of the possibilities.

Here is a compressed index of the book:

• What is ageing and can it be slowed, reversed or eliminated?
• Multiple theories of ageing
• Five deadly diseases (of ageing)
• Animal models (research models)
• Key opinion leaders
• Target therapies
• Life expectancy and demographics
• Companies (to invest in)
• What you can do yourself to stay healthy/young

Greg Bailey (investor and entrepreneur) gives an introduction to the book. He argues that we’re at a breakthrough moment in ageing research. Where first the focus was on lifestyle interventions (adding a few healthy years, possibly even extending lifespan a bit), it’s now on drugs/therapies that might extend life by much more. He argues that inflammation and insulin resistance are most probably two mechanisms that have much to do with how we age (but the evidence isn’t clear yet how the causal effects work). He personally takes metformin, a statin, baby aspirin, with fish oil, curcumin, vitamin D and B, nicotinamide mononucleotide (NMN) and episodic calcium.

Longevity is taking flight, just as flight was some 100 years ago. Two key issues are:

1. How to cure or tame diseases that become more prevalent and devastating as people age
2. How to research ageing as a unitary disease in itself

To do this, we must look at the cells itself, an area that is now exploding (with investment and discoveries). It’s also relatively recently that more and more researches have begun to see ageing as a disease. Before, and still for many people, the separate diseases are treated as such. The effects of a longer healthy lifespan will result in lower health costs, more productivity and economic growth.

Definition: Ageing is marked by a progressive loss of physical integrity, with lessened functionality and increased vulnerability to death.

The Human Cell Atlas aims to identify every cell in every tissue (about 37 trillion in total).

What is Ageing and can it be Slowed, Reversed or Eliminated?

“The short answers: it’s bad, maybe, possibly, and probably not!”

The goal of most researchers is to extend healthy lifespan, to have a very short period of illness. Most current therapies are focussed on this, only soon will we also be able to (radically) extend lifespan in general. The current ‘hard’ ceiling proposed in the book is 115 years. They speak of a bridge being built, one that connects/makes us survive until we find the ‘real/long-term’ solutions.

One change in attitudes is that we can see ageing as a single disease complex. Regenerative medicine will allow us to restore our bodies to the best/optimal state. Thus we should focus on the causes of ageing (e.g. chronic inflammation, cell breakdown, mitochondrial DNA damage, stem cell depletion, cellular senescence).

The authors speak about why it’s now the right time to invest. They argue that genomic sequencing, the imminent appearance of therapies make this the right moment.

Human research takes very long (we don’t die quickly) and is very expensive. Yeast, worms, and mice models are sometimes good proxies (and the best we have now).

“Already, we can, and are, reducing the risk of dying from the diseases of ageing. For instance, cardiovascular disease (CVD) related deaths and cancer deaths are each falling in developed countries by about 2 to 4% per annum.“

“Ageing is rigorously described as senescence, the progressive degradation of bodily functions.”

Changes/mutation at the beginning of life may help us, but be detrimental later in life (Medawar-Williams Theory).

“Molecules become unbound, genes become inefficient, waste products (cellular debris) build up… shortening of telomeres, reduced mitochondrial function (limiting energy production), the depletion of the potency of stem cells, and impaired cellular networks.”

“For now there are no specifically approved or recommended treatments to delay or to reverse ageing, other than [caloric restriction/lifestyle changes]”

Yet they are optimistic because we are starting to understand more and more.

“The mitochondria, large structures (‘organelles’) within our cells, are the machines that extract energy from nutrients and store it as adenosine triphosphate (ATP).” With age, they become less effective.

The immune system also becomes less effective (immunosenescence). And other things break down (we get cancer, lose hair, lose balance, type 2 diabetes, etc).

Some types of cells are immortal (e.g. cancer cells). But many of our cells don’t do well at copying after 50 times (too many mistakes). This has been called the Hayflick Limit.

Twin-studies showed that only 20% of date of death was genetic, 80% was environment (not clear how much is (bad)luck and how much is smoking, diet, sleep, etc).

Because of attacks from outside the body (exogenous) and inside (endogenous), we can’t expect our bodies to stay the same (homeostasis). I think that Aubrey de Grey tries to argue that we should make our repair systems so good as to do maintain this. One other aspect to take into account is oxidative stress (reactive oxygen species, ROS). This also increases over time as those free radicals damage cells.

You should be able to estimate your biological age with an epigenetic clock (Horvath, et al.)

“Though we must again stress that our estimates of timeframes are immensely speculative… average life expectancy… will rise from about 73 today to lose to 100 (in 20 years)” … “That said, if you can stay alive for another ten to twenty years, and if you aren’t yet over 75, and if you remain in reasonable health for your age, you have an excellent chance of living to over 110 years old.”

Inflammaging and the declining immune system

“[Inflammaging] describe[s] the aspects of the breakdown of intercellular communication and the gradual failure of the immune system.”

When the innate and learned/adaptive systems begin to fail (called immunosenescence), your body can’t fight infections anymore. In parallel, the immune system is fighting battles it can’t win, leading to persistent inflammation (inflammaging).

In your guts is where most of this happens, this is where your microbiome is (many bacteria). Specifically, the NLRP3 gene (which encodes the cryopyrin protein) becomes less effective.

The B-cells (from bone marrow) and T-cells (ditto, and thymus) also slows with ageing. There are also less ‘naive’ ones, that are open to learning to fight new pathogens. “Immunosurvelliance of persistent viruses and in particular of the cytomegalovirus (CMS), causes stress to T-cells.”

They mention that inflammaging is linked to the big killers. And that resveratrol and metformin might have pathways to suppress/dampen inflammaging.

Growth hormones might also help here (IGF-1) and FGF7. Yet the former is also mentioned elsewhere as a possible negative influence.

Another avenue is to improve our (gut) microbiome. One theory is that in older people the relationship moves from symbiotic to hostile.

Theories of Ageing (views converging)

“… ageing is currently inescapable, that it is characterised by the progressive loss of functioning of our bodies and that it is the principal cause of [deaths from cardiac diseases, cancer, etc].”

The two (broad) views are that 1) ageing is preprogrammed in a way, and 2) that it’s random/stochastic. The former says that there is something in our cells that triggers at some programmed time. The latter says that accumulation of damage, free radicals, etc just heap up over time.

The hallmarks of ageing are (López-Otín, Carlos, et al.)

• Genomic instability
• Telomere attrition
• Epigenetic alterations
• Loss of proteostasis
• Deregulated nutrient sensing
• Mitochondrial dysfunctioning
• Cellular senescence
• Stem cell exhaustion

Proteostasis

This is the loss of homeostasis in the proteome (protein 100-250k we need for life). Proteostasis involves cleaning up misfolded proteins. When this doesn’t happen effectively anymore, diseases start to develop.

Chaperone molecules are proteins (or drugs) that refold misshapen proteins. Two systems are used by the body to destroy misfolded proteins (autophagy-lysosmal and ubiquitin-proteasome systems).

Too many unfolded/misfolded/clumped proteins are implicated in (causing?) Parkinson’s and Alzheimer’s (Powers, et al. 2009).

Boosting proteostasis might increase longevity.

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Phenotypes refer to the physical and behavioural expression of genotypes. You get the latter from your parents, the former is influenced by your environment. Natural selection might select for the ones that reproduce earlier (since they have kids that have their genes), of course this is offset by the chance of those kids surviving. (more is said about evolution and why for instance reptiles don’t seem to age that quick/are still fit at an older age). They also use the example of eunuchs (no chance of reproduction), but not everywhere they lived longer.

Most scientists don’t evoke the second law of thermodynamics (entropy) when talking about ageing. Leonard Hayflick does, and so does Peter Hoffman. Aubrey de Grey argues that people are very good at combatting entropy, but that we should help our cells repair mechanisms.

The disposable soma (body) theory states that ageing occurs due to the accumulation of damage during life. This view argues that we die some time after our ‘usefulness period’ (passing on genes) but leaves the door open to doing repairs etc after that. One correct prediction that it makes, is that in times of low calories, people survive longer (and have fewer kids).

Free radicals, DNA damage and the oxidative theory of ageing states that those three are responsible for ageing. Antioxidants (as applied now) don’t show consistent positive effects. Too much unrepaired DNA does show to change the chromatin (what chromosomes are made of). Caloric restriction (CR) might help a bit (but not much).

The theory of antagonistic pleiotropy argues that a gene variant is beneficial to our survival in early life, becomes harmful as we age. Another view is that ageing does stop at very old ages (and people die of exhaustion?).

The hyperfunction theory argues that the ‘hyperfunction’ of things useful in youth are also causes of ageing/death. Excessive signalling of mTOR and insulin/IGF-1 are examples of this.

The rate of living theory says that the slower the metabolism, the longer an organism lives (Kleiber’s Law).

Most theories contain a piece of the truth. Yet we don’t know at this moment which is best/what is to come (otherwise we would already have solved ageing).

DNA Damage

DNA damage occurs through free radicals (ROS). This happens about 10.000 times per day in humans, in every cell! And one repair takes 10.000 molecules of ATP to repair. (so if my math is correct, 100 million ATP molecules per cell. We have 37 trillion cells, so 3.7e+21 ATP molecules get to work every day. Lol, numbers were calculated in the book too, we have only 50grams of ATP, it’s recycled so fast, we use 180kg per day (overturned)).

“Unrepaired DNA damage is particularly noticeable in non-dividing or slowly dividing cells, such as neuronal, heart and skeletal cells because the mutations tend to persist. Whereas in dividing cells, such as those of the liver, DNA damage that is not repaired will normally automatically induce cell death, though occasionally it can lead to the development of aberrant cancerous cells.”

“ATP liberates energy by being converted into ADP (adenosine diphospahte), by removing one of the phosphate groups. ATP becomes spent when it is converted to ADP. The ADP group is then recycled in the mitochondria, recharged, and re-emerges as ATP and the cycle continues.”

More nuclear DNA damage over time means a greater risk of cancer (which happens with age).

Some (SENS) argue that mitochondrial DNA (mtDNA) mutations in slowly dividing cells are causative of ageing.

The Deadly Quintet

Cardiovascular diseases

Deaths from cardiovascular diseases (CVD) are falling worldwide. In the US this is 20% in the last 20 years (per capita). LDL (bad cholesterol) is a major factor in the formation of heart diseases. Statins (David Sinclair also argues) are a wonderful discovery that helps combat this. (Although food and lifestyle interventions might prevent it in the first place)

“Statins reduce the amount of bad cholesterol int he blood, and so lessen the amount of arterial blockage from the build-up of plaques. Statins also change the heart structure, reducing thickness and volume and reducing the chance of a heart attack.”

Many other interventions related to CVD are mentioned in the book.

Cancer in re(treatment)

“In industrialised nations, about one in two people will develop a form of cancer during their lifetimes, and generally between the ages of 40 and 80. Just under 8 million people die of cancer worldwide each year.”

Immunotherapy is the treatment where the immune system is stimulated to better fight cancer (and this is also how our bodies fight pre-cancerous cells normally). (analogy to a car) “you first have to release the brake, then press on the accelerator and steer where you’d like to go”.

Early therapies only did the first (accelerate), this involved giving patients immune cytokines (which promptly attacked other cells and lead to deadly inflammation). But if the patient did survive, there were long term benefits (cancer not coming back).

CLTA4 is a more targetted (at cancer cells) version of this process.

Analysts predict that 60% of cancers can ben managed by immunotherapies.

Another approach in this direction is CAR-T (chimeric antigen T-cell receptors). Here antibodies are taken outside of the body and manipulated in a lab (and enhanced of course).

Breathing easier in old age – respiratory disease

“[A]ge reduces lung elasticity, respiratory strength and the efficiency of the chest wall in respiration.”

Smoking is a leading cause of respiratory disease. About 10 million people die of this each year.

The categories are:

1. Diseases of the airways (asthma, COPD, bronchitis)
2. Diseases of the lung tissues (pneumonia, asbestos)
3. Pulmonary circulatory diseases (blood vessels get clogged)
4. Lung cancers

Intervention at the genetic level might be a solution for some of these (e.g. COPD). These are at least a decade away according to the authors.

Diabetes – sweet news ahead

Note: authors might consider Alzheimers as a type of diabetes.

Today 8% of the adult population worldwide has diabetes type 2 (450 million people). Diabetes is associated with many (if not all) ageing diseases (as cause). This is all lifestyle-induced…

Diabetes causes 5 million deaths per year.

Type 1 has a genetic component and affects 1% of people worldwide, it’s medically controlled with insulin. Type 2 starts with insulin resistance, obesity and insufficient exercise are the main causes. Lifestyle changes can reverse it (dieting and exercising). A short period of fasting could reverse type 2 and type 1 diabetes (Valter Longo, The Longevity Diet), in mice!

Metformin was originally developed to combat type 2 diabetes.

The book mentions many other types of drug-interventions (mostly related to insulin) for type 1 and 2.

Don’t forget – the long road for dementia

“[T]he prevalence of dementia and neurodegeneration is actually falling in the developed world.” (1/5th in England and Wales in the span of 22 years).

The different kinds of dementia:

1. Alzheimer’s 62%
2. Vascular dementia 17%
3. Mixed dementia 10%
4. Dementia with Lewy bodies 4%
5. Other 3%
6. Parkinson’s disease 2%
7. Frontotemporal dementia 2%

“About 32% of people over 85 years old in the US have been diagnosed with Alzheimer’s.” There are 50 million people living with dementia (130 million in 2050 if no new interventions).

Statins don’t protect against dementia. It is characterized (but maybe not causes) by the build-up of protein (Lewy bodies, amyloid plaques, protein tangles) between cells.

There is a strong link between diabetes and dementia. Poor diets might be a cause (processed foods). Gluten is probably ok for 99% of people (not linked).

“It is thought that the accumulation of misfolded proteins is the result of the failure of the so-called chaperone system, whereby proteins are guided into their 3D structures by helper molecules. The failure of autophagy to remove these misfolded proteins, as well as damaged organelles, through lysosomal degradation aggravates the situation in both Alzheimer’s (tau peptides) and in Parkinson’s (a-synuclein protein aggregation).

“About 70% of Alzheimer’s is genetic, so that means about 30% comes from environmental factors.”

There is currently no cure (and many failed) fo Parkinson’s. What we do know is that exercise is good (induces autophagy and clearance of amyloid plaques and tau protein tangles). Genetic interventions will also come with time.

Animal Models

The elegance of works, the fruits of fly research, mouse hunts, and the leavening of yeast

Shorter-lived animals can (with some caveats) be very good proxies for humans (we live too long). Fruit flies, roundworms, mice, and baker’s yeast are some of the most used animals.

One problem with this is that they were selected for short lifespans in the first place. Wild mice, for instance, live much longer than the lab mice. The homogenous(ness) also doesn’t reflect real-life well. Also, telomerase isn’t a (lifespan) issue for mice.

Another avenue of research is to look at long-lived animals and see what mechanisms they have that keep them healthy. The hydra can regenerate indefinitely and FOXO genes seem to be an interesting avenue of research.

Insilico Medicine is a company that uses machine learning (ML) that uses human gene expressions to see if there is a biological age (and where you are on that scale). They also use ML to find new drugs/molecular structures.

Fertility is also a topic of interest and improving IVF (with NAD+ precursors) and getting women ovulating after menopause again is being explored.

Autophagy is the way cells get rid of garbage, “[it] delivers unwanted components from within the cytoplasm to the lysosome, which reduces them to amino acids and other cellular building blocks.” As we age, this process breaks down more often/becomes less efficient. Spermidine might work to keep it going better (reduce inflammation, clean cells).

The Buck Institute is the world’s first independent research institution focused on using ground-breaking research to prevent and cure age-related chronic diseases.

Biomarkers of ageing are quantitative variable indicators of biological age. Inflammation agents, glucose metabolism biomarkers, and others are examples. This type of indicator might better predict health and care needs than chronological age.

Key Opinion Leaders

David Sinclair (Life Biosciences) – Both researcher and entrepreneur (12 longevity companies).

Nir Barzilai – Metformin (2019 trail, also cautionary note: higher Alzheimers?), HDL.

Aubrey de Grey – See Ending Aging, SENS research foundation.

Leonard Hayflick & Laura Deming – Entropy, animal models don’t translate well.

Craig Venter – Sequence Human Genome, Human Longevity Inc.

(etc)

Targets in Ageing

Rules and regulations

If ageing was classified as a disease, things would go smoother. 90% of drugs fail in clinical trials. Phase 2 is to test efficacy (and here most drugs die).

Ageing Vampires

Young blood for old mice! works. The mice experiments probably worked because of the parabiosis (stitching together), the liver and circulatory system (not per se only/primarily the blood itself). But maybe not for humans. Possibly you can administer osteopontin (a protein that is lacking at older age, no transfusion needed). More research is needed.

Caloric restriction

Unpleasant and doesn’t seem to really work for people (i.e. doesn’t translate well from animal models), and is hard/impossible to adhere to. Intermittent fasting might have same/better effect.

AMPK and Metformin

Metformin (antidiabetic drug), and the gene AMPK (adenosine monophosphate activated kinase). Possible life extension effects, TAME trail on the way.

mTOR, Rapamycin and Rapalogs

mTOR stands for mechanistic target of rapamycin, 2 pathways, MTORC1 is the focus. But has side-effects in humans, rapalogs (analogues) are being developed.

Sestrins

A family of proteins, expressed when stressed (activate AMPK).

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