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Longevity and Age-related Diseases

Chronic age-related diseases (ARDs) include cancer, Alzheimer`s disease, Parkinson’s disease, osteoarthritis, rheumatoid arthritis, osteoporosis, osteopenia, COPD, maculopathy, sarcopenia, and periodontitis. Typical geriatric syndromes (GSs) comprise frailty, mild cognitive impairment and METABOLIC SYNDROME.

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The central dogma of geroscience – an interdisciplinary science – is that aging and ARDs/GSs share a common set of basic biological mechanisms (Franceschi 2018 ; Sierra 2021); If the same molecular and cellular mechanisms underpin both aging and ARDs/GSs, it stands to reason that the primary target of modern medicine should be to combat aging instead of waiting for the onset of any ARD/GS (McKay 1956): according to this integrative view, ARDs and GSs can be conceptualized as accelerated aging.

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Therefore, aging on one side and ARDs/GSs on the other must be regarded as different trajectories of the same process, but proceeding at a rate that depends on individual genetic backgrounds and lifestyles. 

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 What truly matters is not achieving longevity, but maximizing the time a person enjoys a healthy, disability- and disease-free life, i.e., to maximize health span/compress morbidity /ensure that people can enjoy not just longer lives, but healthier, happier and more productive lives (Irving 2019). Consequently, we should start focusing on a more important parameter than lifespan, such as health-adjusted life expectancy (HALE).

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In 2016, when compared against nine other high-income countries and the EU, the USA came in last in HALE – behind China : at that time the HALE of top-ranking Singapore was 76.2 vs 68.5 for the USA (Batz 2019). It is worth noting that: a) in 2019 life expectancy across 50 US states ranged between 81.3 years for Hawaiians and 74.7 years for West Virginians, and b) in 2016, the gap between life expectancy and HALE was 10 years for the USA and only 6.7 years for Singapore. These statistics clearly show the very substantial gains in HALE of US citizens that might still be achieved.

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Across many countries, people are living longer and as a result, their aging populations are widely believed to represent a demographic challenge. In fact, while the obvious costs are high (health and social care), THE GREAT POTENTIAL BENEFIT - THE SO-CALLED “LONGEVITY DIVIDEND” – IS MUCH OVERLOOKED (Butler 2008; Olshansky S J 2007, 2016, 2018; Scott 2021), and mounting evidence supports the concepts of COMPRESSION OF MORBIDITY and LONGEVITY DIVIDEND:

  • Older people’s socioeconomic impact is already significant ; by 2035 workers aged 50 and over are projected to generate nearly 40% of all earnings across the G20 (Dimitriadis 2020)

  • There is AMPLE POTENTIAL to increase older people's socioeconomic contributions because some of the barriers that they face are avoidable – with the most important being POOR HEALTH 

  • In countries that spend more on health, older people work, volunteer and spend more 

  • In the UK, the old-age dependency ratio has increased for 100 years while the economy has continued to prosper (Bass 1996)

  • Increasing preventative health spending in the UK by just 0.1% can unlock a 9% increase in annual spending by people aged 60+ (Dimitriadis 2020)

  • In Olshansky’s words, “A new approach to public health in a rapidly aging world has been proposed (the longevity dividend), with the idea that extending healthy life by slowing aging may prove to be the most efficient way to combat the fatal and disabling diseases that plague us today”.

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 According to a group of distinguished geroscientists who met at NIH in the Third Geroscience Summit in 2019,“ the economic gains for the US alone from a minor slowdown in aging – originally estimated in 2013 to be about 7.1 trillion USD by 2060 – would be considerably higher today. Moreover, these estimated benefits could be significantly greater if geroscience-guided interventions also diminished the risk of severe COVID-19 and future pandemics involving other pathogens“ (Sierra 2021).

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Indeed, IT IS HIGHLY LIKELY THAT GEROSCIENCE-GUIDED INTERVENTIONS WILL SIGNIFICANTLY DIMINISH THE BURDEN OF COVID-19 AND FUTURE VIRAL PANDEMICS since biological aging has emerged as“ one of the most important modifiable factors of COVID-19“ (Sierra 2021).

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Which are the basic mechanisms shared by aging and ARDs/GSs ? A group of international experts have identified “seven pillars“ that include (Kennedy 2014):

  • Diminished adaptation to stress

  • Loss of proteostasis

  • Stem cell exhaustion

  • Metabolism derangement

  • Macromolecular damage

  • Epigenetic modifications, and

  • Inflammation

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Independently, metabolism derangement has been posited to be the most important mechanism; thus, in 2007 Phoenix and de Grey emphasized the role of metabolism-caused damage and demonstrated that “a simulation based on a biologically realistic model of aging (namely, as THE ACCUMULATION OF MOLECULAR AND CELLULAR DAMAGE) can very precisely describe the pattern of mortality seen in populations with low age-independent mortality” (Phoenix 2007), in 2013 G Alexander Fleming coined the term “metabesity” to describe the constellation of interconnected diseases with METABOLIC ROOTS and in 2016 Lopez-Otin et al. explained in a remarkable paper (“Metabolic control of longevity”) how each of the nine hallmarks of aging is connected to undesirable metabolic alterations : targeting these metabolic underpinnings could be a productive approach to delaying or even preventing, most of the chronic diseases of aging.

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According to de Grey, the best anti-aging strategy should be based on addressing the SEVEN CAUSES OF CELLULAR DAMAGE :

  • Intracellular waste

  • Intercellular waste

  • Stem cell loss

  • Increase in senescent cells

  • Nuclear mutations

  • Mitochondrial mutations

  • Protein cross-links

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We believe that the optimal anti-aging strategy must simultaneously address BOTH the accumulation and repair of metabolism-caused damage and may profitably be guided by consideration of BOTH the “seven pillars” of Kennedy and the seven causes of de Grey ; such dual therapeutic/ prophylactic strategy comprises the following - admittedly somewhat redundant – actions :

  • elimination of waste (intra- and intercellular) and toxins (endogenous and exogenous)

  • elimination of senescent cells and transformed cells

  • prevention of stem cell exhaustion

  • repair of DNA damage and deleterious histone epigenetic modifications

  • optimization of immune function

  • restoration of healthy levels of gasotransmitters and other key signaling molecules

  • minimization of oxidative stress, ER stress, ETC 

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It remarkably and surprisingly turns out that – as pointed out by Perridon et al. (2016) and Wilkie et al. (2021) - H2S “is a key mediator of processes that promote longevity and improve late-life health”, and plays a major role in age-related pathologies and syndromes. Thus, evidence generated mainly between 2000 and 2015 overwhelmingly indicates that H2S exerts direct effects on eight out of the nine “hallmarks of aging” (Lopez-Otin 2013), whereas more recent experimental results strongly support the notion that H2S directly modulates ALL HALLMARKS OF AGING – including telomere attrition (Herrmann 2020, Stock 2021).

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In closing, bibliographic support will be provided for the contribution of H2S to each of the seven above-mentioned healthy longevity-promoting actions :

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More Bibliography

  • Das UN, 2021, “Cell membrane theory of senescence” and the role of bioactive lipids in aging and aging associated diseases and their therapeutic implications, BIOMOLECULES, 11:241

  • Falco’n P et al., 2019, Nutrient sensing and redox balance : GCN2 as a new integrator in aging, OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, Article ID 5730532

  • Fortunato S et al., 2019. First examples of H2S-releasing glycoconjugates : stereoselective synthesis and anticancer activities, BIOCONJUGATE CHEMISTRY, 30(3):614-620

  • Goncharov NV et al., 2017, Markers and biomarkers of the endothelium, OXIDATIVE MEDICINE AND CELLULAR LONGEVITY, Article ID 9759735

  • Lee MB and Kaeberlein M, 2018, Translational geroscience : from invertebrate models to companion animals and human interventions, TRANSL MED AGING, 2:15-29

  • Lee ZW, 2016, Hydrogen sulfide donor as an anti-cancer agent : targeting glucose metabolism and pH imbalance to anticancer cell viability, metastasis, and angiogenesis, Ph.D. DISSERTATION, NATIONAL UNIVERSITY OF SINGAPORE 

  • Li H et al., 2020, Hydrogen sulfide and its donors : novel antitumor and antimetastatic therapies for triple-negative breast cancer, REDOX BIOLOGY, 34:101564

  • Li H et al., 2020, Hydrogen sulfide donating ent-kaurane and spirolactone-type 6,7-seco-ent-karane derivatives : design, synthesis and antiproliferative properties, EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 178:446-457

  • Scott AJ, 2021, The longevity society, LANCET HEALTHY LONGEVITY, 2.e820-827

  • Tabibzadeh S, 2021, From genoprotection to rejuvenation, FRONTIERS IN BIOSCIENCE, LANDMARK, 26:97-162

  • Wang S et al., 2021, The mechanisms of vascular aging, AGING MEDICINE, 4:153-158

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