We are now able to start releasing the results of our first cohort of clients. All clients are anonymised with reference only to their age and past medical history. All clients consented for this information to be published and were under no pressure or obligation to do so.
We aim to share relevant information that is useful for other clinicians and patients to learn from our experiences in promoting healthy behaviours and ultimately behaviours and interventions that slow the rate of aging.
Client 001
Our first client is a 30-year-old male with no significant past medical history. He works in a professional industry with work commitments regularly exceeding 60 hours per week. His main objectives were summarised as becoming ‘generally healthier’ in a manner that was practical and time effective considering his limited free time. And, to ultimately establish daily practices that would slow the rate of biological aging.
After our consultation we were able to further define these goals into several categories:
1. Promotion of skeletal muscle and mitigation of sarcopaenia
2. Optimise metabolic health and avoid diseases of metabolism
3. Improve daily physical and cognitive performance
4. Improve both biological and functional assessments of aging
5. Mitigate unnecessary harms
Why are these goal definitions important?
Aging is a complex and multi-process phenomena across species. In 2013, Linda Partridge, Carlos López-Otín and others established the 9 Hallmarks of Aging to better direct research into the causes of aging. As the authors note:
“Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution.”
The Hallmarks of Aging they described are as follows:
1. Genomic Instability
2. Telomere attrition
3. Epigenetic alterations
4. Loss of proteostasis
5. Deregulated nutrient sensing
6. Mitochondrial dysfunction
7. Cellular senescence
8. Stem cell exhaustion
9. Altered intercellular communication
When we dive into each of these hallmarks, we see that many of them are linked and overlap. Genomic instability (Hallmark No 1) in the form of nuclear DNA damage, of the kind we are sustaining all the time, leads either to DNA repair, apoptosis, or cellular senescence (Hallmark No 7).
Most somatic cells lack telomerases which replicate the terminal ends of linear DNA molecules causing telomere attrition (Hallmark No 2) and this gives cells a natural replicative capacity termed the Hayflick limit upon which a cell becomes senescent (Hallmark No 7 again).
Epigenetic alterations (Hallmark No 3) refer to histone modifications and DNA methylation that controls gene expression. Inhibition of H3K27 histone demethylase in nematodes extends lifespan by influencing genes related to the insulin/IGF-1 signalling pathway (Hallmark No 5). Sirtuins are a family of NAD-dependent protein deacetylases and ADP ribosyltransferases of whose gene expression (Hallmark No 3) is related to rate of aging. Overexpression of SIRT1 in transgenic mice leads to improved genomic stability (Hallmark No 1) and improved nutrient sensing (Hallmark No 5). SIRT6 regulates genome stability, and its expression is inversely correlated with IGF-1 and IGF-1 signalling (Hallmark No 5 again). SIRT3, which can be activated by dietary restriction, is located in mitochondria and deacetylates mitochondrial proteins; improving the capacity to regenerate aged stem cells (Hallmark No 8).
Proteostasis represents the cells’ ability to correctly fold proteins and dysregulation of this process leads to Alzheimer’s disease and Parkinson’s disease among others. Protein folding is mediated by chaperone proteins and these latter proteins fall under the epigenetic control of SIRT1 (Hallmark No 3). Misfolded proteins are cleared by proteolytic mechanisms that decline with aging. Manipulating nutrient sensing pathways (Hallmark No 5) via omega 3 fatty acids, or spermidine, or mTOR inhibitors like rapamycin, leads to increased autophagy and improved proteolytic clearance of misfolded proteins (Hallmark No 4).
The insulin and IGF-1 signalling pathway (IIS pathway) inform cells of the availability of glucose (IGF-1 and insulin both play a similar role here). The IIS pathway leads to downstream control of mTOR complexes, and the FOXO transcription factor family which are both implicated in aging. Dietary restriction (DR) extends lifespan in nematodes, mice and mammals including primates, and part of this effect is due to the impact of DR on the IIS pathway. IIS attenuation is seen in aging animals as a defence against cell damage and optimising this further but not abrogating the pathway leads to increased lifespan (Hallmark No 5). Other nutrient sensors include mTOR, AMPK, and the Sirtuin family; mTOR senses high amino acid levels; AMPK senses low energy states via detecting high AMP levels; Sirtuins detect low energy states by detecting high NAD+ levels. mTOR is expressed as a complex of mTORC1 and mTORC2; inhibition of mTORC1 leads to increased lifespan in some animals. AMPK senses nutrient scarcity and its upregulation inhibits mTORC1. Metformin is a common and low-cost drug that activates AMPK among other processes. SIRT1 (Hallmark No 3) deacetylates and activated PPARʏ coactivator 1α (PGC-1α) that leads to mitochondriogenesis (Hallmark No 6) and improves fatty acid oxidation (Hallmark No 5).
Deficiency in the mitochondrial DNA polymerase ʏ (Hallmark No 1) in mice leads to premature aging and dysfunctional mitochondria (Hallmark No 6). Mitochondrial dysfunction may originate from telomere attrition (Hallmark No 2) and p53 mediated repression of PGC-1α. SIRT1 (Hallmark No 3) eliminated dysfunctional mitochondria via autophagy. Accumulation of damaged mtDNA and oxidation of mitochondrial proteins may also lead to mitochondrial dysfunction. These processes can be overcome by endurance training which improves mitochondrial efficiency as well as dietary fasting (possibly via Hallmark No 5 though likely processes other than DR at play here).
Cellular senescence represents stable cell cycle arrest and such senescent cells accumulate with aging. Senescence is a paradoxical phenomenon where there accumulation in certain tissues is associated with aging and diseases of aging (lung alveolar senescent cells and pulmonary fibrosis) but they also play a role in suppressing tumour formation and promoting wound healing. Senescent cells accumulate due to genomic instability (Hallmark No 1), and telomere attrition (Hallmark No 2). Senescent cells also secrete pro-inflammatory cytokines termed the SASP which drives certain diseases of aging via ‘inflammaging’ (Hallmark No 9).
Haematopoiesis declines with age due to exhaustion of stem cells. This leads to attenuated immune responses (immunosenescence), increased incidence of anaemia and myeloid malignancies. In fact, increased accumulation of senescent cells (Hallmark No 7) and decreased IGF-1 levels (Hallmark No 5) with age may represent attempts to preserve stem cells niches. Inhibition of FGF2 signalling ameliorates stem cell exhaustion and DR may even increase intestinal and muscle stem cell function. Parabiosis experiments where stem cells from younger mice transplanted into older mice extends lifespan and reduces the aging phenotype. Rapamycin may lead to improved stem cell function, in addition to its roles in improving proteostasis (Hallmark No 4) and nutrient sensing (Hallmark No 5).
The final hallmark of altered cellular communication can be seen in the context of the SASP and inflammaging (Hallmark No 7). Inflammaging may also arise from impaired pathogen clearance due to attenuated immune responses (Hallmark No 8), enhanced activation of NF-κB, or defective autophagy (Hallmark No 4). Enhanced activation of the NLRP3 inflammasome and therefore IL-1β, TNF, and interferons is implicated in type 2 diabetes mellitus, obesity, atherosclerosis, and such inflammation may also impair stem cell function (Hallmark No 8).
These Hallmarks of Aging allow us as clinicians to better address aging as a disease and better direct interventions to slow or halt it. Therefore, when it is appropriate, we find it useful to frame a client’s aims and objectives within the above Hallmarks to better outline and clarify our interventions. It is important to note that not all of our interventions are framed in this way, but those clearly relating to aging.
The Hallmarks were created to direct future research in the field of aging but they do provide useful interventions for clinicians today too. For instance, certain drugs (though not limited to these) were identified such as rapamycin, metformin, resveratrol, and spermidine. Certain dietary interventions were detailed such as omega-6 fatty acids, dietary or caloric restriction, and dietary fasting. Exercise interventions such as endurance exercise were covered. And finally, biomarkers not traditionally measured in the clinic were covered such as interleukins and TNF among others.
It is necessary to highlight that these ‘biological’ hallmarks of aging were designed for researchers and not clinicians. Consequently, the clinician has other markers of aging to consider that are not covered in this pivotal 2013 paper. These can be termed, ‘Functional Features of Aging’.
Phenotypically aging is seen as impaired function of tissues and organs. This includes heart failure where the efficiency of left ventricular function is seen (among other features) or inefficiency of diastole. Reduction in cognitive capacity, sometimes manifesting as dementia. Reduced lung volume and forced expiratory volume, leading to reduced exercise capacity and also reduced quality of life via shortness of breath and disordered breathing and impaired sleep. Impaired bone mineral density, combined with reductions in joint proprioception and visuospatial abilities increases the risk of falls and therefore fractures. Neck of femur fractures typically confer a mortality rate of 50% in 1 year. Impaired absorption in the gun, alongside changes in haematopoietic stem cell production leads to anaemias and changes in dietary micronutrient needs.
The clinician must be concerned with the above as they directly relate to morbidity and mortality in patients. Impaired mitochondrial efficiency is important, but it is more relevant to the clinician when it results in heart failure.
In our approach, we look at both features of aging; the 9 Hallmarks and the functional elements of aging too. Furthermore, humans are not aeroplanes. A human is more than merely a sack of proteins but a living person with a personality and temperament and hopes, dreams, fears, and ideas about the world. We must remember that we are treating people and not machines. In all our endeavours we take a holistic approach and always place the patient at the centre of the decision-making process.
We also have a duty to do good (beneficence) and do no harm (non-maleficence). Our interventions are evidence based, and medical decisions are often a complex mix of weighing up various harms; harms from intervening and harms from not intervening. Again, we believe that the patient is the best person to make these decisions, when supported by highly trained medical professionals and when presented with up-to-date evidence with strategies to monitor and mitigate risk.
Returning to the 5 goals we defined earlier, we can now frame them in the context of the Hallmarks of Aging and the Functional Features of Aging described above. The client’s initial stated goals of becoming ‘generally healthier’ and ‘slowing aging’ were non-specific, and in the absence of any other strongly held beliefs or desires, he agreed that proceeding along the Hallmarks of Aging and Functional Features of Aging framework was most in line with his objectives. Were the client to state their objective was to increase muscular explosive power in Olympic Weightlifting, or agility and acceleration to benefit their ability to play tennis; these are different goals that do not necessarily align with delaying or slowing aging (though there may be significant overlap, the ultimate end goals are different, the markers of progress are different, and clinical decisions will be different).
Five goals were then created to reconcile these two frameworks in the context of client 001. The first goal was to promote skeletal muscle and avoid its inverse, sarcopaenia. Patients tend to age in two manners:
1. Gradual deterioration in function
2. Stepwise decline in function
In the first process, muscle slowly diminishes, and muscular strength declines gradually after the age of 40 years of age (sarcopaenia). This slow decline can be mitigated through carefully applied resistance training and hypertrophy training to delay, slow, and offset the decline.
The stepwise deterioration is more sinister. It occurs when a patient suffers an injury leading to rapid muscle catabolism and resultant loss of muscle mass and strength. This may be via a sporting injury that leaves the patient unable to train or even mobilise adequately. If the patient is older, then such a loss in mass and strength may be irreversible and a new functional baseline is reached. In younger patients, an injury may be an Intensive Care Unit stay for reason not directly relating to skeletal muscle or joint integrity (e.g. severe pneumonia) but the process of being bedbound leads to severe muscle loss nonetheless.
In the Functional Features of Aging, skeletal muscle plays a core role in joint stability and preventing joint injury. Muscle also affords us the quality of life to perform everyday activities of living such as bending, lifting objects, climbing stairs, waking up an incline, descending a decline, among others. Skeletal muscle confers metabolic benefits that relate to the Hallmarks of Aging. Reducing fat and replacing it with muscle achieves hormonal changes such as increased insulin sensitivity as well as reducing the components of the SASP and its contributions to inflammaging. By promoting skeletal muscle, we can achieve several goals:
1. Increase strength to augment quality of life today (whether in sport or daily life)
2. Increase strength today to preserve strength into later life (offset the Functional Features of Aging such as falls, or inability to climb stairs, do shopping etc)
3. Increase hypertrophy, to increase strength and preserve strength during sarcopaenia
4. Promote functional ability, strength, explosive power, and endurance in defined activities important to the patient today (typically a chosen sport) and at the extreme of life (bending to pick up a grandchild, lifting an item off a top shelf, carrying shopping bags, swinging a golf club at age 90)
5. Maintenance of bone mineral density (secondary effect of increased skeletal muscle allowing continued high activity levels that encourage bone stress and health)
6. Prevention of diseases of sedentary lifestyle in later life (ischaemic heart disease, type 2 diabetes mellitus, and infections such as bacterial pneumonia and increased vulnerability to respiratory viral infections such as RSV)
7. Achieve metabolic benefits of skeletal muscle
The second goal was to optimise metabolic health and avoid diseases of metabolism. This more closely relates to the Hallmarks of Aging. Cellular goals translate into functional and clinic outcomes. Preserving and promoting autophagy improves proteostasis mechanisms that prevents protein folding diseases such as Parkinson’s disease or Alzheimers dementia. Controlling cellular senescence reduces the risk of fatal pulmonary fibrosis. Reducing the SASP lessens the risk of type 2 diabetes mellitus. With regards to the Hallmarks, we can outline some cellular goals and interventions to achieve this:
1. Promote beneficial epigenetic changes (Hallmark No 3): Carefully controlled dietary protein intake to achieve optimal IGF-1 levels whilst promoting skeletal muscle. Caloric restriction (CR) to promote SIRT3 activation. Ensuring adequate NAD levels to promote sirtuin function.
2. Promote proteostasis (Hallmark No 4): Improve cellular autophagy via optimal fatty acid intake balanced against calorie restriction and considerations of harmful fat intake (such as excessive saturated fat or trans-fats). Adequate dietary or supplemental spermidine. Consideration of mTOR inhibitors such as rapamycin balanced against side effects. Caloric restriction.
3. Optimise nutrient sensing (Hallmark No 5): Caloric restriction with carefully controlled dietary protein intake to achieve optimal IGF-1 levels whilst promoting skeletal muscle. Period stimulation of mTOR via leucine rich meals for skeletal muscle anabolism whilst avoiding chronic mTOR stimulation. Consideration of AMPK activators like metformin. Augment NAD+ levels
4. Promote mitochondrial function: improve NAD+ levels for adequate SIRT1 activation. Regular endurance training. Caloric restriction.
5. Manage cellular senescence: complex given the limited knowledge of the paradoxical nature of senescence. Has both pro and anti-tumorigenic properties. Some role for senomorphic and senolytic drugs such as fisetin and quercetin in a small subset of patients.
6. Mitigate stem cell exhaustion: Caloric restriction and carefully controlled IGF-1 levels. Consideration of rapamycin in some patients.
7. Avoid and monitor negative intercellular communication: monitor SASP via regular biomarkers and further medical interventions and imaging as needed. Consideration of senomorphic drugs
The third goal is to optimise the daily performance of the client in both physical activities and cognitive activities. This acknowledges the need to live in the present and the need to perform at our best today. Interventions needs to achieve both desired physical and cognitive outcomes and interventions should not cause impaired physical or cognitive performance. Some subsets of patients cannot tolerate time restricted feeding where it leads to fatigue and poor performance, others gain greatly from it. Some patients are liable to feel worse with biguanide use such as metformin, particularly causing lactic acidosis and impairing sport performance.
Patients also respond differently to illnesses. For instance, upper respiratory tract infections barely cause any symptoms in some patients but have significant impact on cognitive performance in others. Such considerations allow us to tailor when to intervene and when not to intervene, balancing the risk-reward profile of giving/withholding a treatment.
Interventions must also be tailored to the individual; not just their unique biology but also their social factors (lifestyle, work, physical environment) and psychological factors. Exercise plans must match the resources available and be acceptable to the patient and their time and other constraints. Our interventions should enhance the lives of our clients and not add unnecessary burden where it is not welcome. All plans must be uniquely constructed to match each individual.
The fourth goal covers improving biological and functional markers of aging. That is an improvement in an epigenetic clock is useful, but not if the patients mitral valve regurgitation is worsening their cardiac function. Context is key. We must combine both traditional clinical markers of health which have stood the test of time for a reason, alongside novel and emerging biomarkers as well as markers typically confined to research studies. We must assess all markers but avoid a narrow lens that becomes obsessed with certain results at the expense of others. We not only apply biological markers but also functional assessments previously only used in elite sport, to patients to slow aging. We take a research scientist centric view, a physician centric view, and an elite athlete centric view. Combining them we achieve optimal outcomes.
The final goal is to avoid unnecessary harm. We are surrounded by factors negatively influencing our health, from air pollution to ionising radiation on aeroplane flights to CT scanners. UV radiation and carcinogens in alcohol, food, and tobacco smoke. Added sugar in meals and drinks. It is imperative to identify, highlight, reduce and then mitigate such harms. Heavy metals in cacao or olive oil, or mercury dental fillings are all implicated in disease and accelerating biological aging.
Harms may also come from perceived ‘good’ interventions such as exercise. If done with poor form and technique, resistance training may damage joints, muscles, and ligaments. If inadequate rest periods, dietary intake to match exercise intensity, or impaired sleep, these may all deleteriously effect the individual and lead to harm. All harms must be mitigated where possible.
With these goals identified, we created a first cycle of interventions for client 001. We will detail these interventions and their results over the coming articles.