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The nine hallmarks of aging are shown together with those therapeutic strategies for which there are proof of principle in mice.

The Nine Hallmarks of Ageing: A Guide to Thriving Through Time

Feeling the first whispers of ageing? You’re not alone. As high achievers between 30 and 60, you’ve built extraordinary lives, but aches and pains can start to whisper about decline. The good news? Ageing isn’t a downhill slide. By understanding the nine hallmarks of ageing, you can empower yourself to optimise your health, performance, and well-being – and leave those whispers in the dust.

Remember, I’m not a replacement for medical advice. But with my 20+ years as a Strength & Conditioning (S&C) and physical therapy specialist, working with elite athletes and busy professionals like you, I’ve seen the incredible impact of understanding ageing’s underlying processes. So, let’s dive into the nine hallmarks:

The Hallmarks of Aging

1. Genomic Instability: Think of your DNA as your body’s blueprint. With time, errors can creep in, causing instability. But, healthy habits like exercise and good nutrition can minimise these errors and keep your blueprint strong.

Genomic and Epigenomic Alterations
A) Genomic instability and telomere attrition. Endogenous or exogenous agents can stimulate a variety of DNA lesions that are schematically represented on one single chromosome. Such lesions can by repaired by a variety of mechanisms. Excessive DNA damage or insufficient DNA repair favors the aging process. Note that both nuclear DNA and mitochondrial DNA (not represented here) are subjected to age-associated genomic alterations. BER, base excision repair; HR, homologous recombination; NER, nucleotide excision repair; NHEJ, non-homologous end joining; MMR, mismatch repair; ROS, reactive oxygen species; TLS, translesion synthesis; SAC, spindle assembly checkpoint.

B) Epigenetic alterations. Alterations in the acetylation and methylation of DNA or histones, as well as of other chromatin-associated proteins, can induce epigenetic changes that contribute to the aging process.

2. Telomere Attrition: Telomeres are like the protective caps on your chromosomes. As they shorten with age, cellular decline accelerates. Fortunately, stress management, a balanced diet, and regular physical activity can slow this shortening and protect your precious cellular caps.

3. Epigenetic Alterations: Imagine chemical switches flipping on and off, regulating your genes. Ageing can disrupt these switches, impacting how your genes function. But here’s the exciting part: nutritional tweaks, exercise, and mindfulness practices can help “reset” these switches, optimizing gene expression and keeping your body humming.

4. Loss of Protein Homeostasis: Proteins are the workhorses of your body. Ageing can disrupt their production and function, leading to various issues. The answer? Strength training, a balanced diet rich in protein, and quality sleep support protein health, keeping your body’s workhorses strong.

Loss of Proteostasis
Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock proteins (HSP) or targeted to destruction by the ubiquitin-proteasome or lysosomal (autophagic) pathways. The autophagic pathways include recognition of unfolded proteins by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated autophagy) or sequestration of damaged proteins and organelles in autophagosomes that later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins can lead to their accumulation and aggregation, resulting in proteotoxic effects.

5. Deregulated Nutrient Sensing: Your body’s ability to sense and respond to nutrients like glucose and amino acids changes with age. This can lead to imbalances and health problems. But fear not! Mindful eating, intermittent fasting (consult your doctor first!), and targeted supplementation can help regulate nutrient sensing, keeping your body’s internal compass calibrated.

Metabolic Alterations
A) Deregulated nutrient-sensing. 
Overview of the somatroph axis involving growth hormone (GH) and the insulin/insulin growth factor 1 (IGF-1) signaling pathway, and its relationship to dietary restriction and aging. Molecules that favor aging are shown in orange, while molecules with anti-aging properties are shown in light green.

B) Mitochondrial dysfunction. Mitochondrial function becomes perturbed by aging-associated mtDNA mutations, reduced mitochondriogenesis, destabilization of the electron transport chain (ETC) complexes, altered mitochondrial dynamics or defective quality control by mitophagy. Stress signals and defective mitochondrial function generate ROS that, below a certain threshold, induce survival signals to restore cellular homeostasis, but at higher or continued levels can contribute to aging. Similarly, mild mitochondrial damage can induce a hormetic response (mitohormesis) that triggers adaptive compensatory processes.

6. Mitochondrial Dysfunction: Mitochondria are your cellular powerhouses, converting food into energy. Ageing can impair their function, leading to fatigue and health issues. The good news? Regular exercise, antioxidant-rich foods, and stress management can optimize mitochondrial function, keeping your energy levels soaring.

7. Cellular Senescence: Imagine some of your cells getting stuck in “retirement mode,” no longer dividing and contributing. This senescence can disrupt tissue function. But there’s hope! Exercise, plant-based diets, and specific supplements can promote the removal of senescent cells, keeping your tissues youthful and vibrant.

Cellular Senescence, Stem Cell Exhaustion and Altered Intercellular Communication
A) Cellular senescence. In young organisms, cellular senescence prevents the proliferation of damaged cells, thus protecting from cancer and contributing to tissue homeostasis. In old organisms, the pervasive damage and the deficient clearance and replenishment of senescent cells results in their accumulation, and this has a number of deleterious effects on tissue homeostasis that contribute to aging.
B) Stem cell exhaustion. Consequences of the exhaustion of hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), satellite cells and intestinal epithelial stem cells (IESCs) are exemplified.
C) Altered intercellular communication. Examples of altered intercellular communication associated with aging.

8. Stem Cell Exhaustion: Your body has stem cells that replenish and repair tissues. Ageing can decrease their number and function. The answer? Lifestyle interventions like exercise, good sleep, and stress management can support stem cell health, keeping your body’s repair system robust.

9. Altered Intercellular Communication: Cells need to talk to each other to function properly. Ageing can disrupt this communication, leading to tissue dysfunction. But social connection, healthy relationships, and engaging activities can stimulate communication pathways, keeping your body’s internal network strong.

Functional Interconnections between the Hallmarks of Aging
The proposed nine hallmarks of aging are grouped into three categories. In the top, those hallmarks considered to be the primary causes of cellular damage. In the middle, those considered to be part of compensatory or antagonistic responses to the damage. These responses initially mitigate the damage, but eventually, if chronic or exacerbated, they become deleterious themselves. In the bottom, there are integrative hallmarks that are the end result of the previous two groups of hallmarks and are ultimately responsible for the functional decline associated with aging.

Remember, you’re not just ageing, you’re evolving. By understanding these nine hallmarks and taking action, you can empower yourself to thrive through time. I’m here to support you every step of the way, with test-based prescriptions and proven strategies that fit your busy schedule. Forget ineffective approaches; let’s optimize your health, performance, and well-being, together.

Together, let’s rewrite the narrative of ageing. Are you ready?

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