When you are in your twenties being old is something that happens to other people. By the age of 47 the average person has already used up 75% of their healthy life expectancy, according to uk.gov statistics*. You’ve worked hard to get to this stage of life: now the challenge is to be able to enjoy it for more than just a decade and a half.

As science unravels the 9 hallmarks of ageing there is solid evidence to show that there is plenty you can do if you act early enough. Feeling better today AND living healthier for longer is the fundamental purpose behind humanpeople.

We have done the hard work of sifting through the science and presenting it for you in a digestible format for you so you can make up your own mind and can start making a change today. At the bottom of this article you will find links to the original research.

* Healthy life expectancy is 62 years old, the age the average person in the UK lives before they have a significant irreversible disease

Major milestones in longevity

The last decade has led to major advances in our understanding of the biological process of ageing. We now not only understand how a number of these mechanisms work, but we also have a good idea of how to slow them down, stop them, or even reverse them. When you have read the remarkable progress that has been made in the last decade the idea of a human not only living to 150, but also being healthy at that age does not seem so far fetched. You can even get started on influencing a number of these mechanisms today.

2012: Prof. Yamanaka wins Nobel Prize for reversing the maturation process in cells by turning skin cells into stem cells using what are referred to as “Yamanaka” factors.

2013: Landmark publication “The (9)Hallmarks of Aging” in Cell sets out a framework for the biological processes of ageing.

2015: Revolutionary TAME trial gets FDA approval for the process of anti-ageing.

2018: FDA reclassifies ageing as a disease.

2020: Harvard Professor reverses age-related blindness in old mice using some of the Yamanaka factors.

The 9 Hallmarks of Ageing

Ageing is a programmed biological process by which we lose the integrity of our cells, leading to an impaired ability to function with an increased vulnerability to death. This deterioration is the main risk factor for human illnesses such as dementia, heart disease, cancer and diabetes – conditions found in the aged, not the young.

Ageing research has advanced rapidly over the last decade with the discovery that ageing is at least partially controlled by genetic pathways and our biochemistry. These processes are being unraveled along with the ability to manipulate and repair them.

20 extra years of living or 20 years of dying?

The idea of a long life is something that may seem appealing. However, does an old age with poor mobility, multiple health issues and a poor quality of life really appeal? Or, is a life with minimal health issues what we really seek?

Although life expectancy in the UK is 82 years, healthy life expectancy is only 62, according to the Office of National Statistics (23). That means the average person has a significant irreversible disease by the age of 62. The last 20 years for the average person is lived in ill health.

It doesn’t need to be that way.

If you don’t want to look and feel old as you advance in years then keep reading to discover some simple hacks, based on the latest science, that you can implement today.

If you have been following the longevity space for some time you will be aware that this research is now entering the mainstream with serious institutes and researchers involved.

To name just three:

1. Shinki Yamanaka, a Nobel Prize Winner for his work on stem cell research;
2. Professor David Sinclair, a genetics Professor and director of the Centre for Biology of Ageing at Harvard Medical School, author of Lifespan and podcaster;
3. Nir Barzilai, director of the Institute for Ageing Research at Einstein College of Medicine, who was instrumental in getting the FDA to reclassify ageing as a disease, and is now Scientific Director of the TAME trial.

Major institutions are producing impactful studies that have won Nobel Prizes. Research is being published in leading journals such as Nature, Science, and the New England Journal Medicine.

The billionaires seeking eternal youth – Jeff Bezos and Google join the race for eternal youth.

There is nothing new in the ultra-rich seeking eternal life and there is some serious investment going into anti-ageing companies because the science of ageing is now a valid area of research. Big pharma can see how lucrative it is. The major players are: Altos Labs, which is being backed by Jeff Bezos with Prof Yamanaka as chairperson; Calico Labs, backed by Google with hundreds of millions of dollars; and Cambrian.

We explore some of the major advances in recent years and have included links to the relevant publications in the bibliography at the end of this article:

• We will start by looking at groundbreaking stem cell research
• The role of epigenetics in ageing
• The discovery of three major anti-ageing pathways.
• The things you can start using today to live both better and longer

2012: Nobel Prize for making stem cells in the lab

In 2012 Prof Shinj Yamanaka received the Nobel Prize for discovering how to biologically reprogramme cells (1). His work on stem cells was groundbreaking and set the basis for regenerative medicine.

Stem cells in hair and skin produce cellular offspring that then turn into skin and hair cells, but why does the original stem cell itself not change? There must be something stopping it and if that could be discovered, could it be possible to then reverse the process?

So, starting off with 24 genes they narrowed it down to just four genes that, when inserted into mature cells, turned them into immature stem cells. These four genes are now known as the Yamanaka factors (2). His lab turned skin cells (fibroblasts) into stem cells.

Why is this such a big deal? Well, when placed in the right environment, stem cells can then turn into any cell in the body, including ones that we struggle to grow, like nerve cells. Stem cells are a source of new young cells that can be used to replace older ones that have stopped functioning properly. It allows us to grow new healthy tissue in a laboratory and means that scientists and doctors have stem cells to study and use to further their understanding of how to reverse the ageing process in cells and tissue.

2018/9: The FDA accepts ageing as a disease.

The World Health Organisation has reclassified Ageing in their latest classification, ICD11 in 2019. The US and FDA implemented this classification in 2022.

The MG2A classification has recognised ageing and “ageing associated decline in intrinsic capacity.”

Prior to this the FDA and the NIH in the US had accepted ageing as a condition for clinical trials. The acceptance of the TAME trial took this a step further as this accepted increased longevity as a clinical end point.

They recognised that ageing was a biological process that could be slowed, stopped and reversed. in short it could be treated.

Why do I say momentous? Well, it now allows for scientific research into anti-ageing. The discovery of anti-ageing treatments will be lucrative and therefore billions in research is now pouring into the sector.

This opens the way not only for ethical approval to conduct trials for also an indication that increased age can be a therapeutic target. Previously ethical committees could not allow proper clinical trials to be targeted at reducing ageing as they are only approved for medical indications (10).

The first large scale anti-ageing trial starts with a cheap common drug

The first large study, called the TAME trial (targeting ageing with metformin), is now underway.

Diabetics have a lower life expectancy due to the damage high glucose does to lots of tissues in the body. However, this has been found to not always be the case: diabetics actually have a higher life expectancy when taking metformin. Approval has now been given by the FDA in the US to test low dose metformin in non-diabetics to see if this inexpensive drug will increase life expectancy. It looks promising and you can read more about it here TAME trial (11).

2020: No blind mice – Harvard Professor reverses blindness in old mice.

Fast forward to 2020 and an article published in the leading medical journal Nature by a team of researchers led by Professor of Genetics at Harvard and leading anti-ageing researcher, Prof. David Sinclair, caused quite a stir.

The article explained how they used three of the Yamanaka factors to do just that: they managed to reverse old age sight loss in mice. During the process they also managed to partially regrow the optic nerve (9). As a word of caution, this is just the first major study to use this method and it is a long way from mice to men. Often things cannot be replicated in humans, but it is nevertheless extremely promising.

Each cell contains all of our genetic information, but only uses a small amount of it at a time

Joint winner of the Nobel Prize with Yamanaka was an English developmental biologist called Sir John Gurdon. In 1962 he removed the nucleus from an intestinal cell of a mature frog and implanted it into an egg from a female frog to obtain living tadpoles – the tadpoles were clones. He demonstrated that although the nucleus was extracted from a mature intestinal cell it nonetheless carried all of the genetic information (DNA) to make a whole frog (3).

So we now know that each cell contains the whole genetic code, but we also know that an intestinal cell does not need to produce the same enzymes and proteins as a skin cell or a brain cell, for example. Therefore each cell only reads a few “pages” of the genetic code. It knows what to read by following the genes that are bookmarked or tagged. The essential code for each gene is “tagged” (by attaching a methyl group) to tell the DNA reader what to read (4). This tagging is referred to as epigenetics.

What is epigenetics and the epigenome?

Understanding genetics and epigenetics is key to understanding how to control ageing. Changes in our DNA and epigenetics are crucial features of ageing. It can be confusing, so the explanatory video on link below is well worth watching.

This 1 min 47 sec video from the university of Utah gives a great explanation of what Epigenetics and the Epigenome is (opens in new tab).

Imagine our genetic code was represented by an enormous book with 20,000 pages. Visualise each page as a set of instructions representing a gene.

Firstly, there are subtle differences between the instructions between each person – this is a variation of our genetic code. The differences are small and there is about a 0.1% variation from person to person.

Secondly, the process by which these genes or pages are read is regulated by bookmarking or tagging, and we refer to this process as epigenetics.

Certain pages of the book are kept tightly shut so they cannot be read by the cell. That means that the cell cannot read the instructions for making structures that are not relevant to its purpose. The epigenome can be instructed to change these tags in response to other messengers in the body. For example, hormone messengers during puberty instruct new pages to be opened and others to be closed.

If by accident some pages are open that shouldn’t be, then the cell starts to produce structures or proteins that it shouldn’t.

Epigenetics is the study of how our genes are affected by our lifestyle and environment. Unlike genetic changes, epigenetic changes are reversible and do not change our DNA sequence, but they can change how our body reads a DNA sequence.

Epigenetics and ageing.

A major part of ageing is when this tagging system becomes faulty – we call this epigenetic drift (5). Skin cells start to behave like muscle cells, or liver cells, or stop functioning altogether. When that happens they lose their function. Often the cell doesn’t die and is resistant to dying, but it does stop dividing and loses function. These are called zombie cells or “senescent cells”. When an organ has a high amount of senescent cells it stops functioning properly (6).

Fixing the DNA tagging system and reducing drift is therefore essential to healthy ageing. What’s great is that we also know that activating the mechanisms to do this can be done through fasting mimicking diet (“FMD”), exercise, cold exposure, and supplementation.

For example: when this epigenetic drift occurs in the skin the aged fibroblasts (skin cells) slowly lose their ability to produce healthy collagen and elastin. So the skin gets thinner with age. If we remove these senescent cells then we start to produce cells that make thick healthy skin again. It is easy to measure this in skin, as explained below, but the same process happens in organs all over the body (7).

To measure this in skin, a B-galactoside assay can be used to stain skin cells that have become senescent. We therefore know that there is an age-dependent correlation between senescence and ageing. Removing those inert senescent cells is a key part of healthy ageing. (7)

One way to remove these senescent cells is through fasting. Valter Longo, Professor of Gerontology and Director of the Longevity Institute at the University of California, was nominated for a Nobel Prize for his work on fasting. He showed that in prolonged fasting survival mechanisms kick in and we start to break down abnormal cells for energy. Healthy well-functioning cells are spared and senescent cells and abnormal cells, including tumour cells, are removed. This leads to enhanced cellular regeneration, cognitive performance, and healthspan (8).

Slowing and repairing epigenetic drift and the three major anti-ageing pathways that affect lifespan.

Sirtuin genes encode for a set of proteins. A key feature is that they repair DNA and how genes are expressed ie they maintain normal epigenetic behaviour. They are heavily reliant on a molecule called NAD+ to function. When NAD+ is low their ability to function is reduced and ageing is accelerated. There are seven of these: SIRT1 and SIRT6 are the most studied in relation to longevity. As well as helping to regulate and repair DNA, they control inflammation and antioxidant defence. Activation of SIRT1 in mice has been shown to increase lifespan by 16%. (20)

AMPK is a major regulator of energy production, metabolism, and autophagy. Autophagy is a process by which a cell breaks down and destroys old, damaged, or abnormal proteins and other substances and is therefore extremely important in maintaining normal function. Energy in the body is made in a chemical form called adenosine triphosphate (“ATP”). When it detects that ATP is low it boosts systems to break down fat and old senescent cells (autophagy) to generate more ATP. However, this can also be activated through behaviour like exercise, as well as through certain supplements (21).

mTOR is an enzyme that modifies other proteins involved in regulation of cell growth and metabolism (22). It detects nutrient abundance in the body, particularly the branched chain amino acids found in red meats, insulin from high sugar meals, and testosterone. If you are looking to build muscle you want a lot of mTOR and it activates various hormones. It also increases metabolism and growth. However, too much mTOR is linked to a shortened lifespan, cancers, and chronic health issues. mTOR inhibition occurs during intermittent fasting and can be brought on by medicines or supplements like metformin, berberine, PQQ and silymarin that reduce insulin.

What anti-ageing approaches can you start today?

Sufficient studies and research have now been done to give us an idea of what works, or what is likely to work, and importantly HOW it works. Much of this work has been focused on altering the three well studied anti-ageing pathways mentioned above: sirtuins, AMPK, and mTOR. If you want to know more about these, Prof David Sinclair has a great podcast called Lifespan.

All the clinical studies listed below have been published since 2021, which shows how quickly things are moving.

1. Mimicking adversity i.e. making the body think that “times are hard” turns on these genes. There are several things we can do to mimic adversity, such as those listed below. Certain medicines and supplements also activate these longevity mechanisms.
   • Intermittent fasting tricks the body into thinking that food is scarce. This suppresses the mTOR pathways (a good thing) and activates the AMPK pathway. (12).
   • Intentional exposure to cold. The best results seem to come from both hot AND cold – clearly the Scandinavians have been on to something for some time (13). Exposure to cold also increases dopamine levels in the brain and adrenaline. So you can feel better, at least once you are out of the cold, AND live longer.
   • Hyperbaric high oxygen environments are all the rage in California. Early research shows that it can also activate the anti-ageing pathways (14).
2. Diet and supplementation
   1. Low glucose levels, which can be achieved by intermittent fasting or by using drugs like metformin and supplements. Berberine is a non-pharmaceutical that has a very similar property to metformin. When taken at a daily dose of 500-1000mg (15) it stabilises blood sugar levels and can also help lower cholesterol. It may, however, reduce energy levels, so if you are training intensively it may be best to skip it on these days.
   2. NMN is currently the superstar supplement of anti-ageing because it improves focus and boosts energy as well as being a strong anti-ageing candidate. It is the precursor for NAD and has exploded onto the market. That means better energy AND longevity. Recommended daily dosage is 500mg, but some people, including Prof. David Sinclair, take 1g (16).
   3. Resveratrol is the second safe supplement with a lot of research that has been shown to activate sirtuin genes. This is also a major part of Prof. Sinclair’s personal regime. Daily dosages range from 150-500mg of trans-resveratrol. It is important to take it with food to enhance absorption – yoghurt is an easy way to do this if you don’t like eating breakfast (17).
3. Others
   1. Rapamycin could be a very effective molecule, but there are safety concerns around dosage, so it is still very experimental (18). It is a potent inhibitor of MTOR, but the strong blockage seems to cause other issues such as insulin resistance.

Yamanaka factors: still a long way from a human trial, but animal studies so far have been effective (1). If this technology is perfected then the ability to rejuvenate aged organs, the holy grail of anti-ageing, may well be possible.

Bibliography

1. Yamanaka factors – four factors that could changing aging research, our biological age and life itself Longevity Technology.
2. Yamanaka factors critically regulate the developmental signaling network in mouse embryonic stem cells Cell Res 2009
3. John B Gurdon Embryo transplant
4. Epigenetics: Reversible tags Nature 2013
5. Age-associated epigenetic drift: implications, and a case of epigenetic thrift? Hum Mol Genet 2013
6. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype Front. Cell Dev. Biol., 29 March 2021
7. A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
8. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance and healthspan
9. Reprogramming to recover youthful epigenetic information and restore vision Nature Dec 2020
10. Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization Aging Cell 2022
11. TAME Targeting the Biology of Ageing the Tame Trial
12. Fasting and fasting-mimicking treatment activate SIRT1/LXRα and alleviate diabetes-induced systemic and microvascular dysfunction Diabetologia 2021
13. NAD + /sirtuin metabolism is enhanced in response to cold-induced changes in lipid metabolism in mouse liver FEBS Lett 2021
14. Hyperbaric oxygen via mediating SIRT1-induced deacetylation of HMGB1 improved cReperfusion inj/reperfusion injury Eur J Neurosci 2021
15. Berberine Improves Cognitive Deficiency and Muscular Dysfunction via Activation of the AMPK/SIRT1/PGC-1a Pathway in Skeletal Muscle from Naturally Aging Rats
16. Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects Geroscience 2020
17. Mechanism of human SIRT1 activation by resveratrol
18. Rapamycin for longevity: opinion article Aging 2019
19. DNA methylation age of human tissues and cell types Horvath Steve
20. Sirtuins, a promising target in slowing down the ageing process Biogerontology 2017
21. The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism Nat Cell Biol 2011
22. mTOR as a central regulator of lifespan and aging F1000 Res 2019
23. Chapter 1: life expectancy and healthy life expectancy ONS gov.uk

We are a team of Doctors, nutritionists, web developers and scientists that are obsessed with making new technology relevant and accessible to you.

As technology for analysing our DNA, gut and current health reaches out in to the general public we feel that there is a lack of understanding of what it means and how to use it and we want to be able to help you do that by putting it all together to give you a proper evidence based answer.

We want to put a bit of medical sense in to all these high tech tests and explode some myths and introduce some facts about all of these tests.

Ultimately a balanced healthy diet, sleep and exercise are all keystones to a healthy body and mind but sometimes that just isn’t possible in our busy lives and we feel that with regards to nutrition there is an enormous number of people who just don’t have the time to cook a perfect meal twice a day and that they are being badly let down.

We want to offer a few hacks to help.