Intersection of the pathogenic molecular changes caused by aging and estrogen deficiency and in the development of osteoporosis in both sexes

Life expectancy has increased dramatically over the past two centuries, making the proportion of elderly humans
among the global population higher than any time in history. Recent advances in our understanding of
the biology of aging, on the other hand, have revealed that aging, per se, is a seminal culprit in the development
of many diseases. It remains, therefore, unclear whether increased life expectancy can be accompanied
by postponement of functional limitations and disability. For the bone and mineral metabolism field in particular,
it is imperative to find out whether skeletal involution and osteoporosis – one of the most common diseases
of old age – are inexorable accompaniments of longevity; or whether they can be prevented, or at least
slowed, by targeting molecular pathways and mechanisms of aging, so that “bone health span” can increase in
tandem with lifespan. The urgency to meet this challenge is magnified by the fact that in spite of the emergence
of several new anti-osteoporosis drugs during the last 40 years, the optimal duration of the available therapies
and their long-term safety remain matters of conjecture and some concern.
In my presentation, I will review basic and clinical research advances and genetic insights from humans and
rodents, indicating that the overarching cause of the inv olution of the mammalian skeleton and the degenerative
diseases that accompany it, including the fracture syndrome of osteoporosis, is aging. Bone intrinsic mechanisms,
including mitochondria dysfunction, oxidative stress, declining autophagy, DNA damage, osteoprogenitor
and osteocyte senescence, SASP, and lipid peroxidation may be primary culprits. Bone-extrinsic mechanisms,
i.e. age-related changes in other organs and tissues, such as the ovaries and the innate immune system,
are contributory. In the mouse model, the effects of aging are independent of estrogen deficiency and mechanistically
distinct. The extent to which these two mechanisms contribute to bone fragility in humans remains
to be determined. Nonetheless, in view of evidence that progressive bone loss in both sexes begins long before
sex steroid changes, and evolutionary conserved aging mechanisms are inexorable, the diagnostic term “postmenopausal
osteoporosis” is misleading and needs reappraisal. Several new classes of drugs targeting age-related
mechanisms, including senolytics and natural antibodies against oxidation specific epitopes, have the potential
to treat more than one age-related disease, including osteoporosis, simultaneously. Skeletal involution,
therefore, is not inexorable and may, indeed, be slowed or prevented by targeting aging mechanisms.manolagas

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